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Open Access Highly Accessed 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

David J Klein1*, Debra Foster2, Christa A Schorr3, Kazem Kazempour4, Paul M Walker2 and R Phillip Dellinger3

Author Affiliations

1 Department of Critical Care, and the Keenan Research Centre, Li Ka Shing Knowledge Institute, 4-054C Donnelly Wing, St Michael’s Hospital, 30 Bond Street, Toronto, Ontario M5B 1 W8, Canada

2 Spectral Diagnostics Inc., -2 The West Mall, Toronto, Ontario M9C 1C2, Canada

3 Cooper University Hospital, Cooper Medical School Rowan University, 1 Cooper Plaza, Camden, NJ 08103, USA

4 Amarex Clinical Research, 20201 Century Blvd, 4th Floor, Germantown, MD 20874, USA

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Trials 2014, 15:218  doi:10.1186/1745-6215-15-218

Published: 11 June 2014

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.

Keywords:
Endotoxin; Endotoxemia; Septic shock; Polymyxin-B; Hemoperfusion; Theragnostics