Interim Analysis triggered futility

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

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

Each enrolled patient will be randomized to receive either L citrulline or placebo throughout all administrations in the study. Patients will receive:

1. an L-citrulline bolus of 150 mg/kg or placebo at the initiation of cardiopulmonary bypass
2. the addition L-citrulline or placebo to maintain a steady state target concentration of approximately 100 μmol/L of L-Citrulline or placebo during cardiopulmonary bypass
3. an L-citrulline bolus of 10 mg/kg or placebo 30 minutes after decannulation from cardiopulmonary bypass, followed immediately by a 9 mg/kg/hour continuous L-citrulline infusion or placebo for up to 48 hours post-first dose. The infusion rate will be adjusted (up or down titration of drug infusion) to achieve a target steady state concentration of 100 µmol/L.

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

Inclusion Criteria:

• Patients, parents, or legal guardian willing and able to sign informed consent
• Male and female subjects aged ≤18 years of age (females of child-bearing potential willing to practice an acceptable form of birth control)
• Patients undergoing cardiopulmonary bypass for repair of a large unrestrictive ventricular septal defect, an ostium primum/secundum atrial septal defect, or a partial or complete atrioventricular septal defect
• Pre-operative echocardiogram confirming cardiovascular anatomy and defect to be repaired

Exclusion Criteria:

• Evidence of pulmonary artery or vein abnormalities that will not be addressed surgically. Specific abnormalities excluded include:

  • 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 IV 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; Sexually active females of child-bearing potential must be willing to practice an acceptable method of birth control for the duration of study participation (e.g. oral contraceptive, hormonal implant, intra-uterine device)

• 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.

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

Randomization via an IWRS. Study drug or placebo will be prepared and labeled with the appropriate subject identifiers only; no information that would reveal the contents of the dose to be administered (active versus placebo) will be included on the label. Study drug (citrulline or placebo) will be provided in either identical syringes or bags and mask labeled. The bags will be the same size, shape, and fluid clarity, and hence masked to both investigators and staff administering the drug. Only the pharmacist and the unblinded monitor responsible for performing drug accountability (a different monitor than the person performing routine data monitoring) will be aware of the treatment assignment.