Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2014

Open Access 01-12-2014 | Study protocol

The EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock): study protocol for a randomized controlled trial

Authors: David J Klein, Debra Foster, Christa A Schorr, Kazem Kazempour, Paul M Walker, R Phillip Dellinger

Published in: Trials | Issue 1/2014

Login to get access

Abstract

Background

Septic shock is common and has unacceptably high morbidity, mortality, and associated cost with numerous failed attempts at developing effective therapies. Endotoxin, one of the most potent mediators of sepsis, is found in high levels in approximately 50% of patients with septic shock. Polymyxin B (PMX) hemoperfusion has been shown in numerous studies to successfully remove endotoxin and potentially improve outcomes. EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock) is a theragnostic trial (matching blood measurement to treatment capability) of PMX hemoperfusion in patients with septic shock and confirmed endotoxemia as measured by the endotoxin activity assay (EAA).

Methods

EUPHRATES is a pivotal regulatory trial that is multi-centered, placebo-controlled and blinded. The trial is being conducted in fifty ICUs in the United States and Canada and is powered to enroll 360 patients. Patients with persistent septic shock despite adequate fluid resuscitation on vasopressors for more than 2 and less than 30 hours are eligible for measurement of the EAA. Those with EAA ≥0.60 are eligible to be randomized to treatment with two sessions of PMX hemoperfusion 24 hours apart. The primary endpoint for the trial is 28-day all-cause mortality.

Discussion

Unique features of the trial include absence of systemic inflammatory response (SIRS) criteria as a requirement for inclusion, use of the EAA to confirm endotoxemia as a requisite for treatment, and use of a detailed “façade” hemoperfusion event as a blinding mechanism. The outcomes of the second interim analysis included a resizing of the trial to 650 patients and the addition of an exclusion criterion of subjects with multiple organ dysfunction score (MODS) ≤ 9. Results are anticipated in 2016.

Trial registration

Clinicaltrials.gov identifier: NCT01046669. Registered: January 8, 2010.
Appendix
Available only for authorised users
Literature
1.
Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med. 2003, 348: 138-150. 10.1056/NEJMra021333.CrossRefPubMed
2.
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001, 29: 1303-1310. 10.1097/00003246-200107000-00002.CrossRefPubMed
3.
Suffredini AF, Munford RS: Novel therapies for septic shock over the past 4 decades. JAMA. 2011, 306: 194-199.CrossRefPubMed
4.
Angus DC, Mira JP, Vincent JL: Improving clinical trials in the critically ill. Crit Care Med. 2010, 38: 527-532. 10.1097/CCM.0b013e3181c0259d.CrossRefPubMed
5.
Marshall JC, Foster D, Vincent JL, Cook DJ, Cohen J, Dellinger RP, Opal S, Abraham E, Brett SJ, Smith T, Mehta S, Derzko A: Diagnostic and prognostic mplications of endotoxemia in critical illness: results of the MEDIC study. J Infect Dis. 2004, 190: 527-534. 10.1086/422254.CrossRefPubMed
6.
Opal SM, Cohen J: Clinical gram-positive sepsis: does it fundamentally differ from gram-negative bacterial sepsis?. Crit Care Med. 1999, 27: 1608-1616. 10.1097/00003246-199908000-00039.CrossRefPubMed
7.
Klein DJ, Derzko A, Foster D, Seely AJ, Brunet F, Romaschin AD, Marshall JC: Daily variation in endotoxin levels is associated with increased organ failure in critically ill patients. Shock. 2007, 28: 524-529.PubMed
8.
9.
Ziegler EJ, McCutchan JA, Fierer J, Glauser MP, Sadoff JC, Douglas H, Braude AI: Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. N Engl J Med. 1982, 307: 1225-1230. 10.1056/NEJM198211113072001.CrossRefPubMed
10.
Greenman RL, Schein RM, Martin MA, Wenzel RP, MacIntyre NR, Emmanuel G, Chmel H, Kohler RB, McCarthy M, Plouffe J, Russell JA, Hollender E, Immerman R, Pfaller M, Sheetz C, Jebson P, Houston A, Rehak D, Empson P, Ireland J, Narain S, Rashkin JE, Jacobs RA, Octavio J, Coleman R, Kenyon VS, Yangco BG, Toney JF, Edwards J, Crislip M: A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. The XOMA Sepsis Study Group. JAMA. 1991, 266: 1097-1102. 10.1001/jama.1991.03470080067031.CrossRefPubMed
11.
Ziegler EJ, Fisher CJ, Sprung CL, Straube RC, Sadoff JC, Foulke GE, Wortel CH, Fink MP, Dellinger RP, Teng NN, Allen E, Berger HJ, Knatterud GL, LoBuglio AF, Smith CR, and the HA-1A Sepsis Study Group: Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N Engl J Med. 1991, 324: 429-436. 10.1056/NEJM199102143240701.CrossRefPubMed
12.
McCloskey RV, Straube RC, Sanders C, Smith SM, Smith CR: Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group. Ann Intern Med. 1994, 121: 1-5. 10.7326/0003-4819-121-1-199407010-00001.CrossRefPubMed
13.
Angus DC, Birmingham MC, Balk RA, Scannon PJ, Collins D, Kruse JA, Graham DR, Dedhia HV, Homann S, MacIntyre N: E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators. JAMA. 2000, 283: 1723-1730. 10.1001/jama.283.13.1723.CrossRefPubMed
14.
Rice TW, Wheeler AP, Bernard GR, Vincent JL, Angus DC, Aikawa N, Demeyer I, Sainati S, Amlot N, Cao C, Ii M, Matsuda H, Mouri K, Cohen J: A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Critl Care Med. 2010, 38: 1685-1694. 10.1097/CCM.0b013e3181e7c5c9.CrossRef
15.
Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, Wittebole X, Dugernier T, Perrotin D, Tidswell M, Jauregui L, Krell K, Pachl J, Takahashi T, Peckelsen C, Cordasco E, Chang CS, Oeyen S, Aikawa N, Maruyama T, Schein R, Kalil AC, Van Nuffelen M, Lynn M, Rossignol DP, Gogate J, Roberts MB, Wheeler JL, Vincent JL, for the ACCESS Study Group: Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA. 2013, 309: 1154-1162. 10.1001/jama.2013.2194.CrossRefPubMed
16.
Dellinger RP, Tomayko JF, Angus DC, Opal S, Cupo MA, McDermott S, Ducher A, Calandra T, Cohen J, for the Lipid Infusion and Patient Outcomes in Sepsis (LIPOS) Investigators: Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial. Crit Care Med. 2009, 37: 2929-2938. 10.1097/CCM.0b013e3181b0266c.CrossRefPubMed
17.
Davies B, Cohen J: Endotoxin removal devices for the treatment of sepsis and septic shock. Lancet Infect Dis. 2011, 11: 65-71. 10.1016/S1473-3099(10)70220-6.CrossRefPubMed
18.
Cruz D, Perazella M, Bellomo R, de Cal M, Polanco N, Corradi V, Lentini P, Nalesso F, Ueno T, Ranieri V, Ronco C: Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review. Crit Care. 2007, 11: 1-12.CrossRef
19.
Cruz DN, Antonelli M, Fumagalli R, Foltran F, Brienza N, Donati A, Malcangi V, Petrini F, Volta G, Bobbio Pallavicini FM, Rottoli F, Giunta F, Ronco C: Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA. 2009, 301: 2445-2452. 10.1001/jama.2009.856.CrossRefPubMed
20.
Kellum JA, Uchino S: International differences in the treatment of sepsis: are they justified?. JAMA. 2009, 301: 2496-2497. 10.1001/jama.2009.850.CrossRefPubMed
21.
Arnold RC, Shapiro NI, Jones AE, Schorr C, Pope J, Casner E, Parrillo JE, Dellinger RP: Multi-center study of early lactate clearance as a determinant of survival in patients with presumed Sspsis. Shock. 2008, 32: 35-39.CrossRef
22.
Cook R, Cook D, Tilley J, Lee K, Marshall J, Canadian Critical Care Trials Group: Multiple organ dysfunction: baseline and serial component scores. Crit Care Med. 2001, 29: 2046-2050. 10.1097/00003246-200111000-00002.CrossRefPubMed
23.
Warnock DG: Towards a definition and classification of acute kidney injury. J Am Soc Nephrol. 2005, 16: 3149-3150. 10.1681/ASN.2005090934.CrossRefPubMed
24.
Levy MM, ellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, Schorr C, Artigas A, Ramsay G, Beale R, Parker MM, Gerlach H, Reinhart K, Silva E, Harvey M, Regan S, Angus DC, Surviving Sepsis Campaign:The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med. 2010, 38: 367-374. 10.1097/CCM.0b013e3181cb0cdc.CrossRefPubMed
25.
Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL, International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; World Federation of Societies of Intensive and Critical Care Medicine: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008, 36: 296-327. 10.1097/01.CCM.0000298158.12101.41.CrossRefPubMed
26.
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R, Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup: Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013, 41: 580-637. 10.1097/CCM.0b013e31827e83af.CrossRefPubMed
27.
Marshall JC, Walker PM, Foster DM, Harris D, Ribeiro M, Paice J, Romaschin AD, Derzko AN: Measurement of endotoxin activity in critically ill patients using whole blood neutrophil dependent chemiluminescence. Crit Care. 2002, 6: 342-348. 10.1186/cc1522.CrossRefPubMedPubMedCentral
28.
O’Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics. 1979, 35: 549-556. 10.2307/2530245.CrossRefPubMed
29.
Agresti A: Categorical Data Analysis. 1990, New York: Wiley
30.
Vincent JL: Dear SIRS, I’m sorry to say that I don’t like you. Crit Care Med. 1997, 25: 372-374. 10.1097/00003246-199702000-00029.CrossRefPubMed
31.
Fdr P, Courtine E, Cariou A, Mira J-P: Toward theragnostics. Crit Care Med. 2009, 37: S50-S58. 10.1097/CCM.0b013e3181921349.CrossRef
32.
Macklin R: The ethical problems with sham surgery in clinical research. N Engl J Med. 1999, 341: 992-996. 10.1056/NEJM199909233411312.CrossRefPubMed
Metadata
Title
The EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock): study protocol for a randomized controlled trial
Authors
David J Klein
Debra Foster
Christa A Schorr
Kazem Kazempour
Paul M Walker
R Phillip Dellinger
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Trials / Issue 1/2014
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/1745-6215-15-218

Other articles of this Issue 1/2014

Trials 1/2014 Go to the issue

Study protocol

Antibiotic rotation strategies to reduce antimicrobial resistance in Gram-negative bacteria in European intensive care units: study protocol for a cluster-randomized crossover controlled trial

Study protocol

Implementing comprehensive prevention of mother-to-child transmission and HIV prevention for South African couples: study protocol for a randomized controlled trial

Study protocol

Efficacy and safety of pamidronate in Modic type 1 changes: study protocol for a prospective randomized controlled clinical trial

Study protocol

Economic evaluation of the prophylaxis for thromboembolism in critical care trial (E-PROTECT): study protocol for a randomized controlled trial

Research

Intervention to reduce excessive alcohol consumption and improve comorbidity outcomes in hypertensive or depressed primary care patients: two parallel cluster randomized feasibility trials

Study protocol

Evolutionary cognitive therapy versus standard cognitive therapy for depression: a protocol for a blinded, randomized, superiority clinical trial