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

Alan E. Jones, Michael A. Puskarich, Nathan I. Shapiro, Faheem W. Guirgis, Michael Runyon, Jason Y. Adams, Robert Sherwin, Ryan Arnold, Brian W. Roberts, Michael C. Kurz, Henry E. Wang, Jeffrey Kline, D. Mark Courtney, Stephen Trzeciak, Sarah A. Sterling, Utsav Nandi, Deepti Patki, Kert Viele

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Importance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT01665092.

Original languageEnglish (US)
Pages (from-to)e186076
JournalJAMA network open
Volume1
Issue number8
DOIs
StatePublished - Dec 7 2018

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Carnitine
Septic Shock
Sepsis
Randomized Controlled Trials
Placebos
Organ Dysfunction Scores
Therapeutics
Mortality
Phase III Clinical Trials
Lactic Acid
Fatty Acids
Outcome Assessment (Health Care)
Clinical Trials
Glucose

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Effect of Levocarnitine vs Placebo as an Adjunctive Treatment for Septic Shock : The Rapid Administration of Carnitine in Sepsis (RACE) Randomized Clinical Trial. / Jones, Alan E.; Puskarich, Michael A.; Shapiro, Nathan I.; Guirgis, Faheem W.; Runyon, Michael; Adams, Jason Y.; Sherwin, Robert; Arnold, Ryan; Roberts, Brian W.; Kurz, Michael C.; Wang, Henry E.; Kline, Jeffrey; Courtney, D. Mark; Trzeciak, Stephen; Sterling, Sarah A.; Nandi, Utsav; Patki, Deepti; Viele, Kert.

In: JAMA network open, Vol. 1, No. 8, 07.12.2018, p. e186076.

Research output: Contribution to journalArticle

Jones, AE, Puskarich, MA, Shapiro, NI, Guirgis, FW, Runyon, M, Adams, JY, Sherwin, R, Arnold, R, Roberts, BW, Kurz, MC, Wang, HE, Kline, J, Courtney, DM, Trzeciak, S, Sterling, SA, Nandi, U, Patki, D & 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, vol. 1, no. 8, pp. e186076. https://doi.org/10.1001/jamanetworkopen.2018.6076
Jones, Alan E. ; Puskarich, Michael A. ; Shapiro, Nathan I. ; Guirgis, Faheem W. ; Runyon, Michael ; Adams, Jason Y. ; Sherwin, Robert ; Arnold, Ryan ; Roberts, Brian W. ; Kurz, Michael C. ; Wang, Henry E. ; Kline, Jeffrey ; Courtney, D. Mark ; Trzeciak, Stephen ; Sterling, Sarah A. ; Nandi, Utsav ; Patki, Deepti ; Viele, Kert. / Effect of Levocarnitine vs Placebo as an Adjunctive Treatment for Septic Shock : The Rapid Administration of Carnitine in Sepsis (RACE) Randomized Clinical Trial. In: JAMA network open. 2018 ; Vol. 1, No. 8. pp. e186076.
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abstract = "Importance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT01665092.",
author = "Jones, {Alan E.} and Puskarich, {Michael A.} and Shapiro, {Nathan I.} and Guirgis, {Faheem W.} and Michael Runyon and Adams, {Jason Y.} and Robert Sherwin and Ryan Arnold and Roberts, {Brian W.} and Kurz, {Michael C.} and Wang, {Henry E.} and Jeffrey Kline and Courtney, {D. Mark} and Stephen Trzeciak and Sterling, {Sarah A.} and Utsav Nandi and Deepti Patki and Kert Viele",
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TY - JOUR

T1 - Effect of Levocarnitine vs Placebo as an Adjunctive Treatment for Septic Shock

T2 - The Rapid Administration of Carnitine in Sepsis (RACE) Randomized Clinical Trial

AU - Jones, Alan E.

AU - Puskarich, Michael A.

AU - Shapiro, Nathan I.

AU - Guirgis, Faheem W.

AU - Runyon, Michael

AU - Adams, Jason Y.

AU - Sherwin, Robert

AU - Arnold, Ryan

AU - Roberts, Brian W.

AU - Kurz, Michael C.

AU - Wang, Henry E.

AU - Kline, Jeffrey

AU - Courtney, D. Mark

AU - Trzeciak, Stephen

AU - Sterling, Sarah A.

AU - Nandi, Utsav

AU - Patki, Deepti

AU - Viele, Kert

PY - 2018/12/7

Y1 - 2018/12/7

N2 - Importance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT01665092.

AB - Importance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT01665092.

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