Acute Lung Injury, Severe Sepsis
Conditions
Brief summary
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.
Interventions
DRUGHigh Dose Citrulline
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
DRUGPlacebo
D5W IV fluids at isovolumetric rate (about 15ml/hr)
DRUGLow Dose Citrulline
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.
Sponsors
National Institutes of Health (NIH)
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
13 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Vasopressor Dependency Index | day 4 | 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) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Citrulline Low Dose Citrulline
Low Dose Citrulline: 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. | 26 |
| Placebo Placebo IV infusion
Placebo: D5W IV fluids at isovolumetric rate (about 15ml/hr) | 22 |
| High Dose Citrulline High Dose Citrulline
High Dose Citrulline: 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 | 24 |
| Total | 72 |
Baseline characteristics
| Characteristic | Low Dose Citrulline | Total | High Dose Citrulline | Placebo |
|---|---|---|---|---|
| Age, Continuous | 54.4 years STANDARD_DEVIATION 17.1 | 54.1 years STANDARD_DEVIATION 16.8 | 51.8 years STANDARD_DEVIATION 16.6 | 56.2 years STANDARD_DEVIATION 16.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 9 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 23 Participants | 63 Participants | 22 Participants | 18 Participants |
| Region of Enrollment United States | 26 participants | 72 participants | 24 participants | 22 participants |
| Sex: Female, Male Female | 10 Participants | 30 Participants | 12 Participants | 8 Participants |
| Sex: Female, Male Male | 16 Participants | 42 Participants | 12 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 26 | 5 / 22 | 3 / 24 |
| other Total, other adverse events | 0 / 26 | 0 / 22 | 0 / 24 |
| serious Total, serious adverse events | 5 / 26 | 5 / 22 | 3 / 24 |
Outcome results
Primary
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)
Time frame: day 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Citrulline | Vasopressor Dependency Index | 50.0 mmHg/catecholamine index | Standard Deviation 28.8 |
| Placebo | Vasopressor Dependency Index | 44.4 mmHg/catecholamine index | Standard Deviation 30.9 |
| High Dose Citrulline | Vasopressor Dependency Index | 49.0 mmHg/catecholamine index | Standard Deviation 27.4 |
p-value: 0.86ANOVA