CARING FOR THE CRITICALLY ILL PATIENT Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis The ACCESS Randomized Trial Steven M. Opal, MD Importance Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide Pierre-Francois Laterre, MD (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component Bruno Francois, MD of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. Steven P. LaRosa, MD Objective To determine if eritoran, a TLR4 antagonist, would significantly reduce Derek C. Angus, MD, MPH sepsis-induced mortality. Jean-Paul Mira, MD, PhD Design, Setting, and Participants We performed a randomized, double-blind, Xavier Wittebole, MD placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in Thierry Dugernier, MD September 2011. Dominique Perrotin, MD Interventions Patients with severe sepsis (n=1961) were randomized and treated Mark Tidswell, MD within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n=1304 and n=657 Luis Jauregui, MD patients, respectively. Kenneth Krell, MD Main Outcome Measures The primary end point was 28-day all-cause mortality. Jan Pachl, MD The secondary end points were all-cause mortality at 3, 6, and 12 months after be- Takeshi Takahashi, MD ginning treatment. Claus Peckelsen, MD Results Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was Edward Cordasco, DO no significant difference in the primary end point of 28-day all-cause mortality with Chia-Sheng Chang, MD 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P=.59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, Ϫ1.1; 95% Sandra Oeyen, MD CI, Ϫ5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with Naoki Aikawa, MD, PhD 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Tatsuya Maruyama, MD, PhD Kaplan-Meier analysis of time to death by 1 year, P=.79 (hazard ratio, 0.98; 0.85- 1.13). No significant differences were observed in any of the prespecified subgroups. Roland Schein, MD Adverse events, including secondary infection rates, did not differ between study groups. Andre C. Kalil, MD, MPH Conclusions and Relevance Among patients with severe sepsis, the use of eri- Marc Van Nuffelen, MD toran, compared with placebo, did not result in reduced 28-day mortality. Melvyn Lynn, PhD Trial Registration clinicaltrials.gov Identifier: NCT00334828 JAMA. 2013;309(11):1154-1162 www.jama.com Daniel P. Rossignol, PhD Jogadish Gogate, PhD Author Affiliations are listed at the end of this ar- EVERE SEPSIS, A SYNDROME OF Mary B. Roberts, MS ticle. acute infection complicated by Corresponding Author: Steven M. Opal, MD, Divi- Janice L. Wheeler, BS, RN sion of Infectious Diseases, Memorial Hospital of organ dysfunction, is caused by Rhode Island, 111 Brewster St, Pawtucket, RI 02860 Jean-Louis Vincent, MD, PhD a dysregulated systemic inflam- ([email protected]) Smatory response. Sepsis can progress to Caring for the Critically Ill Patient Section Editor: Derek for the ACCESS Study Group C. Angus, MD, MPH, Contributing Editor, JAMA systemic hypotension (septic shock), ([email protected]). 1154 JAMA, March 20, 2013—Vol 309, No. 11 ©2013 American Medical Association. All rights reserved. Corrected on March 19, 2013 Downloaded From: http://jama.jamanetwork.com/ by a University of Gent / UZGent Kenniscentrum User on 03/26/2013 ERITORAN FOR THE TREATMENT OF SEVERE SEPSIS manifest by hypoperfusion of vital or- non-Japanese; Japanese; other; His- throughout the study. The clinical gans, multiple organ dysfunction, and panic, non-Hispanic) were noted at evaluation committee determined the death.1-3 screening for planned subgroup analy- type, site, and causative organism of The Surviving Sepsis Campaign re- ses of efficacy and safety. Racial cat- sepsis-defining infections. ported decreased mortality based on im- egories were self-reported and these dif- proved supportive care and evidence- ferences were assessed to determine if Study Procedures based guidelines for diagnosis and TLR4 polymorphisms from different A total dose of 98.41 mg eritoran (free timely intervention.4,5 However, mor- populations affected responsiveness to acid) was administered. This amount is tality remains at approximately 30%4 eritoran therapy. equal to the highest total dose of eri- and hospital admissions for severe sep- toran tetrasodium (105 mg) used in the sis have increased.3,5,6 Thus, improve- Patient Selection phase 2 severe sepsis study.15 Eritoran ments in care for severe sepsis remain Patients who were at least 18 years old was administered intravenously as a load- a priority. with early severe sepsis or septic shock ing dose of 26.24 mg (6.56 mg/h for 4 Lipopolysaccharide (LPS) or endo- and high risk of death were screened for hours), followed by a second loading toxin, the major component of the outer participation. Severe sepsis was de- dose of 13.12 mg (6.56 mg/h for 2 hours) membrane of gram-negative bacteria, is fined as documented evidence of bac- 12 hours later, and 9 maintenance doses a potent stimulator of the inflamma- terial or fungal infection, at least 3 cri- of 6.56 mg (3.28 mg/h for 2 hours) given tory response.7 LPS triggers inflamma- teria for systemic inflammatory response every 12 hours thereafter. Matching pla- tion in gram-negative sepsis. Exces- syndrome (SIRS eAppendix, available at cebo (vehicle) vials, with identical re- sive amounts of gut-derived LPS http://www.jama.com), and at least 1 constitution and infusion instructions to released during intestinal hypoperfu- major organ dysfunction. Septic shock the eritoran vials, were administered on sion are implicated in sepsis caused by was defined as hypotension requiring va- the same schedule. gram-positive and fungal infections.8,9 sopressors (eAppendix). High risk of LPS signaling is initiated by activa- death was defined as having an APACHE Primary and Secondary Outcomes tion of the MD2:toll-like receptor 4 II (Acute Physiology and Chronic Health Survival was ascertained at 28 days (TLR4) on myeloid cells.7,10 Eritoran Evaluation) score of at least 21 and not after beginning treatment (the pri- (E5564), a synthetic analog of lipid A greater than 37. The onset of the first mary outcome measure) and at 3, 6, and a potent and specific antagonist of sepsis-related organ dysfunction had to and 12 months through interviews LPS action, inhibits lipid A binding to occur less than 12 hours before admin- with patients or surrogates. Serum MD2 and terminates MD2/TLR4- istration of the study drug. Key exclu- samples of inflammatory markers mediated signaling invitro, exvivo, and sion criteria are listed in eAppendix. were obtained at baseline, 30 minutes invivo.11-13 In a phase 1 trial, eritoran before the second loading dose, and blocked cytokine responses and clini- Randomization on days 2 and 3. When not normally cal illness in healthy volunteers14 and Eligible patients were assigned by cen- distributed, log-transformation of in a phase 2 trial, eritoran-treated pa- tralized randomization using a com- these data was performed for statisti- tients at high risk of death had lower puterized set of random numbers in a cal analysis. Endotoxin activity assays mortality that was not statistically sig- 2:1 eritoran:placebo ratio. Patients were were performed at baseline in a subset nificant (eritoran 37.5% vs placebo assessed daily until hospital discharge of patients by previously described 56.3%).15 or day 28 after randomization. Long- methods (eAppendix).9 The current trial evaluated the safety term follow-up evaluations occurred at Eritoran efficacy was evaluated in and efficacy of eritoran in reducing mor- 3, 6, and 12 months. prespecified patient subpopulations de- tality in patients with severe sepsis. Critical care and infectious disease fined as follows: baseline APACHE II specialists at 3 clinical coordinating cen- score groups (21-24, Ͼ24-26, Ͼ26- METHODS ters (United States, Belgium, and Ja- 31, and Ͼ31-37); gram-negative vs The ACCESS (a controlled compari- pan) reviewed all screening data with gram-positive infections; infection sites son of eritoran and placebo in patients study sites before enrollment to con- (lung, abdomen, genitourinary, skin/ with severe sepsis) trial was designed firm that patients met all inclusion but soft tissue, primary and catheter- as a randomized, double-blind, placebo- no exclusion criteria. Approval from in- related bacteremia, central nervous sys- controlled, phase 3 clinical study. En- stitutional review or ethics boards was tem, and other); and baseline severity rollment occurred from June 2006 obtained for all sites, and written in- of illness by Sequential Organ Failure through September 2010 in 197 sites formed consent was obtained from all Assessment (SOFA) scores. in North America, Europe, South patients or proxies as required by lo- America, Africa, Asia, and Australia. cal authorities. A clinical evaluation Safety Measures Predefined race and ethnicity informa- committee (eAppendix) performed Electrocardiograms, laboratory mea- tion categories (white; black; Asian, blinded evaluations of procedures surements, and physical examina- ©2013 American Medical Association. All rights reserved. JAMA, March 20, 2013—Vol 309, No. 11 1155 Corrected on March 19, 2013 Downloaded From: http://jama.jamanetwork.com/ by a University of Gent / UZGent Kenniscentrum User on 03/26/2013 ERITORAN FOR THE TREATMENT OF SEVERE SEPSIS tions were performed throughout the Infection-related adverse events were Statistical Analysis active 28-day follow-up period or at closely monitored to assess the poten- A modified intent-to-treat (MITT) hospital discharge.