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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Jones reported receiving grants from the National Institutes of Health (NIH), receiving nonfinancial support from Sigma-Tau Pharmaceuticals, and having a patent pending on markers for sepsis treatment. Dr Puskarich reported receiving grants from the National Institute of General Medical Sciences (NIGMS) and having a patent pending on prediction of l-carnitine drug responsiveness based on metabolic biomarkers. Dr Shapiro reported serving on the advisory board for Baxter International. Dr Guirgis reported receiving grants from the NIGMS. Dr Runyon reported receiving research support from Bristol-Myers Squibb, BRAHMS GmbH, Durata Therapeutics International, Trinity Biotech, Boehringer Ingelheim Pharmaceuticals, Siemens Healthcare Diagnostics, Emergency MCG USA, Janssen Pharmaceutical Companies, and Ortho Clinical Diagnostics; receiving royalties from UpToDate for clinical writing on the topic of genitourinary trauma; and being a member of the editorial board for Academic Emergency Medicine. Dr Sherwin reported receiving grants from the NIH. Dr Arnold reported receiving grants from the NIH, National Library of Medicine, and National Science Foundation. Dr Roberts reported receiving grants from the NIGMS and the National Heart, Lung, and Blood Institute. Dr Kurz reported receiving grants from the NIH. Dr Wang reported receiving grants from the NIH. Dr Kline reported receiving grants from the NIH, Bristol-Myers Squibb, and Janssen Pharmaceutical Companies. Dr Courtney reported receiving grants from the NIGMS. Dr Sterling reported receiving grants from the NIGMS. Dr Viele reported receiving grants and research support from the NIH/University of Mississippi. No other disclosures were reported.

Figures

Figure 1.. Consolidated Standards of Reporting Trials (CONSORT) Study Flow Diagram

CPR indicates cardiopulmonary resuscitation; DNR, do not resuscitate; ITT, intent-to-treat; LAR, legally authorized representative; mITT, modified intent-to-treat; and PP, per-protocol.

Figure 2.. Raw and Fitted Mortality Rates of Patients Treated With Saline Placebo or 6, 12, or 18 g of Levocarnitine Based on the Modified Intent-to-Treat and Per-Protocol Analyses

Error bars represent SDs around raw and model-fitted mortality rates.