Rapid Administration of Carnitine in sEpsis

Study Overview
=================
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.

Official Title
-----------------
Phase 2 Study of Levo-Carnitine for Vasopressor Dependent Septic Shock

Conditions
-----------------
Septic Shock

Intervention / Treatment
-----------------
* Drug: Levo-Carnitine
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Suspected or confirmed infection (examples include but are not limited to: white cells in a normally sterile body fluid; perforated viscus; radiographic evidence of pneumonia in clinical symptoms; a syndrome associated with a high risk of infection e.g. cellulitis, cutaneous abscess, ascending cholangitis, toxic shock syndrome, fever of unknown origin with high suspicion of infectious etiology) Any two of four criteria of systemic inflammatory response as defined by the 2001 ACCP/SCCM Consensus Conference Committee; Recognition of septic shock and initiation of quantitative resuscitation within 24 hours of enrollment; Requirement of high dose vasopressors for ≥4 hours to treat shock: Norepinephrine > 0.05mcg/kg/min; dopamine >10mcg/kg/min; Phenylephrine >0.4 mcg/kg/min; epinephrine > 0.05 mcg/kg/min; Cumulative sequential organ failure assessment (SOFA) score of ≥ 6; Blood lactate level of >2.0 mMol/L. Exclusion Criteria: Age <18 years; Pregnancy or breastfeeding; Any primary diagnosis other than sepsis; Established Do Not Resuscitate status or advanced directives restricting aggressive care or treating physician deems aggressive care unsuitable; Any history of seizures or a known seizure disorder; Any known inborn error of metabolism; Anticipated requirement for surgery that would interfere with the 12 hour infusion time; Active participation in another interventional study; Cardiopulmonary resuscitation (chest compression or defibrillation) prior to enrollment; Known systemic allergy to L-carnitine. Severe immunocompromised state (e.g. subject has neutropenia [receiving cytotoxic chemotherapy with absolute neutrophil count <500/uL or expected to decline to < 500 uL within the next three days). Active Treatment with Coumadin

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Normal saline | Drug: placebo<br> <br> |
| Experimental: Carnitine Low<br>Levo-Carnitine 6g | Drug: Levo-Carnitine<br> <br> |
| Experimental: Carnitine Medium<br>Levo-Carnitine 12 g | Drug: Levo-Carnitine<br> <br> |
| Experimental: Carnitine High<br>Levo-Carnitine 18 g | Drug: Levo-Carnitine<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delta SOFA Score | Sequential Organ Failure Assessment Score (0-24 range). Delta SOFA is calculated as (SOFA Score at 48 hours post enrollment minus SOFA Score at enrollment). A negative value indicates improvement in the score. | 48 hours |