Clinical trial NCT01665092
Conditions: Septic Shock
Sponsor: University of Mississippi Medical Center
Start date: 2013-01-01; Completion date: 2019-03-01
Enrollment: 250 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Prior work has shown that exogenous L-carnitine administration enhances glucose and lactate oxidation, attenuates fatty acid toxicity, and improves endothelial-smooth muscle coupling and cardiac mechanical efficiency. The overall goal of this proposal is to investigate L-carnitine as a novel adjunctive treatment of septic shock. In this study the investigators will test our primary hypothesis: Early adjunctive L-carnitine administration in vasopressor dependent septic shock will significantly reduce cumulative organ failure at 48 hours with an associated decrease in 28-day mortality suggesting the need for further phase III study. To accomplish this the investigators will conduct a phase II, double blinded, placebo controlled, adaptive randomized trial of 250 eligible patients with vasopressor-dependent septic shock. Study subjects will be assigned to one of four arms: low (6g), medium (12g) or high (18g) dose intravenous L-carnitine or placebo for 12 hours as a part of early resuscitative care.

Detailed description:

Arms: arm 1: Normal saline arm 2: Levo-Carnitine 6g arm 3: Levo-Carnitine 12 g arm 4: Levo-Carnitine 18 g
Interventions: intervention 1: Levo-Carnitine intervention 2: placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
Rapid Administration of Carnitine in sEpsis (RACE) 
NCT01665092 
 
May 15, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Study Protocol 
This study was a prospective, randomized, blinded, placebo-controlled, clinical trial utilizing Bayesian 
response-adaptive randomization, and designed to assess the efficacy of L-carnitine to decrease the 
sequential organ failure assessment (SOFA) score of patients with septic shock. SOFA score is an organ 
failure scoring system consisting of 6 physiological systems that ranges from 0-24, and a score of 2 or 
more is required for the diagnosis of sepsis. The trial took place from January 2013 to February 2018 in 
the emergency departments and intensive care units of sixteen large urban medical centers in the 
United States. The research protocol was approved by the local institutional review boards and 
performed in accordance with Good Clinical Practice guidelines. 
Participants 
Patients presenting to the participating centers during the study period with septic shock were assessed 
for inclusion. Criteria for inclusion were patients of age ≥ 18 years with confirmed or presumed 
infection, the presence of two or more systemic inflammatory response criteria, enrollment within 24 
hours of recognition of septic shock with initiation of a standardized sepsis treatment pathway, high 
dose vasopressors (norepinephrine > 0.05 mcg/kg/min; dopamine > 10 mcg/kg/min; phenylephrine >0.4 
mcg/kg/min; epinephrine > 0.05 mcg/kg/min; or any vasopressin dose) to treat shock for ≥ 4 hours at 
the time of enrollment, cumulative sequential organ failure assessment (SOFA) score of  ≥ 6, and blood 
lactate level > 2.0 mmol/L. Patients were excluded if they were pregnant or breastfeeding, had any 
primary diagnosis other than sepsis, had an established do not resuscitate status or advanced directive 
restricting aggressive care, any history of seizures, known inborn error of metabolism, anticipated 
surgery that would interfere with the 12 hour infusion, active participation in another interventional 
trial, cardiopulmonary resuscitation prior to enrollment, known allergy to L-carnitine, severe 
immunocompromised state (absolute neutrophil count <500/uL), or active warfarin treatment. 
Eligible patients were screened 7 days per week using electronic medical record based reports of 
admitted patients receiving both antibiotics and vasopressors and/or pager-based alerts informing study 
staff regarding the initiation of a sepsis treatment pathway (which comprised the screening log), in 
addition to active screening of the emergency department tracking board to facilitate earlier 
identification. Each enrolled patient, or the patient’s legally authorized representative (LAR), provided 
written informed consent prior to randomization and collection of data. 
Treatment Assignment 
After informed consent was obtained, a centralized web-based portal was used to determine treatment 
allocation. Patients were randomly assigned to one of three doses of L-carnitine or saline placebo.  
During an initial “burn in” period of 40 patients, participants were allocated equally among the 
treatment arms. From that point on, interim analyses were conducted every 12 patients. At each interim 
analysis the relative allocation probability of the three active arms were adjusted to be proportional to 
the probability each arm would lead to the greatest improvement in SOFA score. A site-based blocked 
randomization approach ensured that approximately one-third of participants were allocated to the 
control arm throughout the trial to maintain a sufficient allocation to control and to avoid confounding 


from local changes in usual care. Predefined stopping rules for both efficacy and futility were 
determined prior to trial initiation. The statistical rationale and methodology has been published 
previously.  
Treatment Interventions 
 
The three treatment arms consisted of low (6 grams), medium (12 grams), and high (18 grams) 
doses of L-carnitine administered intravenously over a 12-hour period. The control (placebo) consisted 
of an identical volume of 0.9% saline placebo. Following randomization, research pharmacists used a 
web-based portal to determine treatment allocation. Pharmacists were the only individuals not blinded 
to treatment, and had no study-related contact with the investigators or participants. Pharmacists and 
staff prepared either L-carnitine or placebo in identical polypropylene infusion bags with labels including 
the study ID number, patient name, medical record number, and infusion rate. For each dose of L-
carnitine, 33% of the total dose was administered as a 20 mL bolus over 2-3 minutes followed by a fixed 
rate continuous infusion of 1 L over the next 12 hours. The study solution was administered through 
intravenous catheters using FDA-approved medical equipment (IV tubing, IV pumps, etc). Levocarnitine 
was provided by Leadiant Biosciences (Gaithersburg, MD, United States; formerly Sigma Tau 
Pharmaceuticals) and maintained by pharmacy staff, with tracking of lot numbers of L-carnitine 
administered. For safety, clinical physicians could elect to break study blinding, though in no instance did 
this occur. 
 
Assessments and Outcome Measures 
During the study treatment period the patient’s physiologic parameters, laboratory results, and medical 
treatments were recorded. Sex, race, and ethnicity were self-reported. An investigator performed a 
bedside assessment and recorded vital signs, vasopressor requirements, ventilator settings, and 
Glasgow Coma Scale at enrollment, 12, 24 and 48 hours later. At enrollment and 48 hours blood samples 
were sent to the clinical laboratory for platelet count, creatinine, and total bilirubin to ensure capture of 
SOFA score parameters. Non-protocol (clinical) laboratory results obtained between 0 and 48 hours 
were recorded. Patients were followed until hospital discharge or death and then up to one year using 
the patient’s electronic medical record and phone calls to the patient or LAR, crossed referenced with 
the social security death index. Study data were collected and managed using REDCap. 
The primary endpoints were change in SOFA score from enrollment to 48 hours, with negative numbers 
indicating improvement, and 28-day mortality. In the event of early death prior to 48-hours, last-value 
carried forward was utilized. Secondary outcomes included ICU and hospital length of stay and 
percentage of patients undergoing withdrawal of care. Three preplanned blinded interim safety analyses 
were performed: after a burn-in phase of 40 patients, and then after one-third and two-thirds of 
participants were enrolled. The unblinded results were reviewed by an independent Data Safety 
Monitoring Board with the authority to terminate the study for safety concerns or if the predefined 
stopping rules for efficacy or futility were fulfilled. The trial was registered on clinicaltrials.gov 
(NCT01665092) prior to initiation and this report was designed to conform to the recommendations of 
the CONSORT statement. 
 


Statistical Analysis 
The trial was considered positive if 1) the posterior probability of any dose decreasing the SOFA more 
than placebo exceeded 90%, and 2) given (1), there was at least a 30% predictive probability that the 
most promising dose would be successful in reducing 28-day mortality in a subsequent two arm, 2,000 
total patient phase III trial. Based on Monte-Carlo simulation of 30,000 simulated trials enrolling up to 
250 patients, the probability of a positive trial assuming no treatment effect (the type I error rate α) was 
4.3%. The power of the trial (β) was dependent on the true treatment effect. If the true SOFA effects for 
the three L-carnitine arms were 0, 1 and 2, corresponding to mortality effects of 0, 6%, and 12%, then 
the power of the trial was 91.1%. 
Changes in SOFA scores between groups were analyzed using a Bayesian approach, assuming a normal 
dynamic linear model dose response, and posterior probabilities are reported. The normal dynamic 
linear model is a Bayesian analogue to a smoothing spline whose smoothness is determining by a tuning 
parameter. The tuning parameter is given a prior and thus is determined by a combination of the prior 
and the observed data. The prior was selected during the design process to provide a smooth fit while 
maintaining the main features of the observed data. 
 Conditional on a declaration of SOFA reduction, predictive probabilities of success in a subsequent 
phase III trial were calculated using non-informative priors. Except for these primary outcomes, 
remaining data were analyzed using frequentist statistics. Categorical data were compared using Chi-
square tests, while continuous variables were compared with ANOVA or Wilcoxon rank sum based on 
normality. All non-Bayesian tests were 2-sided with p<0.05 considered significant. All trial design 
simulations, interim analyses, and Bayesian statistics were performed using the Fixed and Adaptive 
Clinical Trial Simulator Software (FACTS, Berry Consultants, LLC; Austin, TX, United States),while 
frequentist statistics were conducted using STATA 15.1 (StataCorp LLC, College Station, TX). AEJ and 
MAP had full access to all the data in the study and take responsibility for the integrity of the data and 
the accuracy of the data analysis.