L-citrulline for Prevention of Sequelae of Acute Lung Injury in Pediatrics Undergoing Cardiopulmonary Bypass for Heart Defects

This is a randomized, double-blind, placebo controlled, multicenter study that will compare
the efficacy and safety of L-citrulline versus placebo in subjects undergoing surgery for
congenital heart defects.

Eligible subjects undergoing repair of a large unrestrictive ventricular septal defect (VSD),
a partial or complete atrioventricular septal defect (AVSD), or an ostium primum atrial
septal defect (primum ASD) will be eligible for enrollment in this study.

Each enrolled subject will be randomized to receive either L-citrulline or placebo throughout
all administrations in the study. Subjects will receive an L-citrulline bolus of 150 mg/kg or
placebo at the initiation of cardiopulmonary bypass, the addition of L-citrulline at a
concentration of 200 μmol/L or placebo given as a bolus during bypass. This may be
administered as a one-time bolus or multiple administrations to compensate for fluids
containing L-citrulline that may be removed from the patient during the course of the
operation and thus to maintain the concentration of 200 μmol/L. L-citrulline bolus of 20
mg/kg or placebo 30 minutes after decannulation from cardiopulmonary bypass, followed
immediately by a 9 mg/kg/hr continuous L-citrulline infusion or placebo for up to 48 hours.

The study drug or placebo infusion will be discontinued once invasive arterial blood pressure
monitoring is discontinued or at 48 hours, whichever comes first. Subjects will be followed
until Day 28 or discharge from the hospital, whichever comes first. For subjects discharged
prior to Day 28, a final assessment via telephone will be conducted at Day 28.

Inclusion Criteria:

- Subjects, parents, or legal guardian of the subject who are willing and able to sign
informed consent

- Male and female subjects aged ≤18 years of age

- Infants, children and adolescents undergoing CPB for repair of a large unrestrictive
VSD, an ostium primum ASD, or a partial or complete AVSD

- Pre-operative echocardiogram which confirms the cardiovascular anatomy and defect to
be surgically repaired

Exclusion Criteria:

- Evidence of pulmonary artery or vein abnormalities on the pre-operative echocardiogram
that will not be addressed surgically. Specific abnormalities excluded include the
following:

- Significant pulmonary artery narrowing not amenable to surgical correction

- Previous pulmonary artery stent placement

- Significant left sided AV valve regurgitation not amenable to surgical correction

- Pulmonary venous return abnormalities not amenable to surgical correction

- Pulmonary vein stenosis not amenable to surgical correction

- Preoperative requirement for mechanical ventilation or intravenous inotrope support

- Presence of fixed or idiopathic pulmonary hypertension (i.e. Eisenmenger's Syndrome)
prior to surgical repair

- Pre-operative use of medications to treat pulmonary hypertension

- Pregnancy; Females of child-bearing potential must be willing to participate an
acceptable method of birth control for the duration of study participation (e.g. oral
contraceptive, hormonal implant, intra-uterine device)

- Any condition which, in the opinion of the investigator, might interfere with the
study objectives

- Participation in another clinical trial within 30 days of Screening or while
participating in the current study, including the 28 days of follow-up post study drug
administration