Citrulline in Severe Sepsis

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, phase 2 study to evaluate biochemical, clinical, and safety effects of 2 doses of intravenous L-citrulline compared to placebo in patients with severe sepsis at risk for or with acute lung injury. The hypothesis is that intravenous L-citrulline will decreased the development or progression of acute lung injury in patients with severe sepsis compared to placebo.

Official Title
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Prospective, Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Intravenous Citrulline to Prevent or Mitigate Acute Lung Injury in Patients With Severe Sepsis

Conditions
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Severe Sepsis, Acute Lung Injury

Intervention / Treatment
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* Drug: High Dose Citrulline
* Drug: Placebo
* Drug: Low Dose Citrulline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Severe Sepsis Exclusion Criteria: No Consent Malignant or other irreversible condition Moribund and not expected to survive 48 hours End Stage Liver Disease Enrolled in another IND study Pregnant or breast feeding female Age<13 years old Allergy to citrulline or arginine

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low Dose Citrulline<br>Low Dose Citrulline | Drug: Low Dose Citrulline<br>* Initial intravenous bolus of 10mg/kg (to a maximum of 1500mg) L-citrulline over 10 minutes. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 4.5mg/kg (max 350mg) per hour will be administered through a dedicated intravenous line or port of a multilumen catheter for 4 days.<br>|
| Placebo Comparator: Placebo<br>Placebo IV infusion | Drug: Placebo<br>* D5W IV fluids at isovolumetric rate (about 15ml/hr)<br>|
| Active Comparator: High Dose Citrulline<br>High Dose Citrulline | Drug: High Dose Citrulline<br>* Initial intravenous bolus of 20mg/kg (to a maximum of 1500mg) L-citrulline over 10 minutes. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9mg/kg (max 700mg) per hour will be administered through a dedicated intravenous line or port of a multilumen catheter for 4 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vasopressor Dependency Index | Worst Value of Index measuring blood pressure hourly through study infusion (day 4). Vasopressor index is mean arterial blood pressure divided by catecholamine index (the catecholamine index is a dimensionless variable calculated as (dopamine dose × 1) + (dobutamine dose × 1) + (adrenaline dose × 10) + (noradrenaline × 100) + (phenylephrine dose × 100), where all doses are expressed in ug/kg/min). (Higher is better) | day 4 |