Effect of Levocarnitine vs Placebo as an Adjunctive Treatment for Septic Shock: The Rapid Administration of Carnitine in Sepsis (RACE) Randomized Clinical Trial

dc.contributor.authorJones, Alan E.
dc.contributor.authorPuskarich, Michael A.
dc.contributor.authorShapiro, Nathan I.
dc.contributor.authorGuirgis, Faheem W.
dc.contributor.authorRunyon, Michael
dc.contributor.authorAdams, Jason Y.
dc.contributor.authorSherwin, Robert
dc.contributor.authorArnold, Ryan
dc.contributor.authorRoberts, Brian W.
dc.contributor.authorKurz, Michael C.
dc.contributor.authorWang, Henry E.
dc.contributor.authorKline, Jeffrey A.
dc.contributor.authorCourtney, D. Mark
dc.contributor.authorTrzeciak, Stephen
dc.contributor.authorSterling, Sarah A.
dc.contributor.authorNandi, Utsav
dc.contributor.authorPatki, Deepti
dc.contributor.authorViele, Kert
dc.contributor.departmentEmergency Medicine, School of Medicineen_US
dc.date.accessioned2019-06-26T17:02:47Z
dc.date.available2019-06-26T17:02:47Z
dc.date.issued2018-12-07
dc.description.abstractImportance: Sepsis induces profound metabolic derangements, while exogenous levocarnitine mitigates metabolic dysfunction by enhancing glucose and lactate oxidation and increasing fatty acid shuttling. Previous trials in sepsis suggest beneficial effects of levocarnitine on patient-centered outcomes. Objectives: To test the hypothesis that levocarnitine reduces cumulative organ failure in patients with septic shock at 48 hours and, if present, to estimate the probability that the most efficacious dose will decrease 28-day mortality in a pivotal phase 3 clinical trial. Design, Setting, and Participants: Multicenter adaptive, randomized, blinded, dose-finding, phase 2 clinical trial (Rapid Administration of Carnitine in Sepsis [RACE]). The setting was 16 urban US medical centers. Participants were patients aged 18 years or older admitted from March 5, 2013, to February 5, 2018, with septic shock and moderate organ dysfunction. Interventions: Within 24 hours of identification, patients were assigned to 1 of the following 4 treatments: low (6 g), medium (12 g), or high (18 g) doses of levocarnitine or an equivalent volume of saline placebo administered as a 12-hour infusion. Main Outcomes and Measures: The primary outcome required, first, a greater than 90% posterior probability that the most promising levocarnitine dose decreases the Sequential Organ Failure Assessment (SOFA) score at 48 hours and, second (given having met the first condition), at least a 30% predictive probability of success in reducing 28-day mortality in a subsequent traditional superiority trial to test efficacy. Results: Of the 250 enrolled participants (mean [SD] age, 61.7 [14.8] years; 56.8% male), 35, 34, and 106 patients were adaptively randomized to the low, medium, and high levocarnitine doses, respectively, while 75 patients were randomized to placebo. In the intent-to-treat analysis, the fitted mean (SD) changes in the SOFA score for the low, medium, and high levocarnitine groups were -1.27 (0.49), -1.66 (0.38), and -1.97 (0.32), respectively, vs -1.63 (0.35) in the placebo group. The posterior probability that the 18-g dose is superior to placebo was 0.78, which did not meet the a priori threshold of 0.90. Mortality at 28 days was 45.9% (34 of 74) in the placebo group compared with 43.3% (45 of 104) for the most promising levocarnitine dose (18 g). Similar findings were noted in the per-protocol analysis. Conclusions and Relevance: In this dose-finding, phase 2 adaptive randomized trial, the most efficacious dose of levocarnitine (18 g) did not meaningfully reduce cumulative organ failure at 48 hours.en_US
dc.identifier.citationJones, A. E., Puskarich, M. A., Shapiro, N. I., Guirgis, F. W., Runyon, M., Adams, J. Y., … Viele, K. (2018). Effect of Levocarnitine vs Placebo as an Adjunctive Treatment for Septic Shock: The Rapid Administration of Carnitine in Sepsis (RACE) Randomized Clinical Trial. JAMA network open, 1(8), e186076. doi:10.1001/jamanetworkopen.2018.6076en_US
dc.identifier.urihttps://hdl.handle.net/1805/19685
dc.language.isoen_USen_US
dc.publisherAmerican Medical Associationen_US
dc.relation.isversionof10.1001/jamanetworkopen.2018.6076en_US
dc.relation.journalJAMA Network Openen_US
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States*
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/3.0/us*
dc.sourcePMCen_US
dc.subjectSepsisen_US
dc.subjectLevocarnitineen_US
dc.subjectSequential Organ Failure Assessment (SOFA)en_US
dc.titleEffect of Levocarnitine vs Placebo as an Adjunctive Treatment for Septic Shock: The Rapid Administration of Carnitine in Sepsis (RACE) Randomized Clinical Trialen_US
dc.typeArticleen_US
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