Clinical trial NCT01120964: Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery : Revised Protocol
Official title: Phase IB Double Blind, Randomized, Placebo Controlled Clinical Trial to Determine the Pharmacokinetics and Safety of a Revised Protocol of Intravenous L-Citrulline (Citrupress®) Versus Placebo in Children Undergoing Cardiopulmonary Bypass
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Atrial Septal Defect
Ventricular Septal Defect
Atrioventricular Septal Defect
Lead sponsor: Asklepion Pharmaceuticals, LLC
Sponsor class: INDUSTRY
First posted: 2010-05-11
Enrollment: 22
Sex: ALL
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This clinical trial will determine the safety and effectiveness of intravenous L-citrulline in children undergoing cardiopulmonary bypass during heart surgery. Participants will be randomly assigned to either L-citrulline or a placebo (a substance that has no medicine in it).

Citrulline is a protein building block in the body that can convert into another substance, nitric oxide (NO), which controls blood pressure in the lungs. Increased blood pressure in the lungs can be an important surgical problem; it may also lead to problems following surgery, such as severe high blood pressure in the lungs (pulmonary hypertension), increased time spent on a breathing machine, and a longer stay in the intensive care unit (ICU). The hypothesis of this study is that perioperative supplementation with intravenous citrulline will increase plasma citrulline, arginine and NO metabolites and prevent elevations in the postoperative PVT leading to a decrease in the duration of postoperative invasive mechanical ventilation.

The objective of this study is to determine in a randomized placebo controlled phase IB multicenter clinical trial if a revised protocol of intravenous L-citrulline delivery given perioperatively achieves a plasma citrulline level of \> 100 umol/L in children undergoing surgical repair of an atrial septal defect,ventricular septal defect or an atrioventricular septal defect.

Detailed description: Increased pulmonary vascular tone (PVT) can complicate the postoperative course of the following five surgical procedures for congenital heart defects: 1) unrestrictive ventricular septal defect (VSD) repair; 2) atrioventricular septal (AVSD) repair; 3) arterial switch procedure for transposition of the great arteries (TGA); 4) bidirectional Glenn shunt procedure; and 5) Fontan procedure for single ventricle lesions. PVT is partially controlled by NO. Arginine, the precursor to NO, is a product of the urea cycle. Preliminary data have been presented regarding 169 infants and children who have undergone one of six previous surgical procedures. It was found that urea cycle function and plasma arginine levels were significantly decreased in all participants. Furthermore, participants with increased PVT had significantly lower arginine levels compared to participants with normal PVT. Finally, a genetic single nucleotide polymorphism (SNP) in the rate limiting urea cycle enzyme (carbamyl phosphate synthetase I \[CPSl T1405N\]) appeared to affect postoperative plasma arginine levels and PVT. It is hypothesized that perioperative enhancement of urea cycle function with the key urea cycle intermediate (citrulline) will increase plasma arginine and NO metabolites and prevent elevations in PVT.

Eligibility criteria: Inclusion Criteria:

1. Informed Consent signed by the subject's legal representative
2. Subjects \< 6 years old
3. Subjects undergoing cardiopulmonary bypass for repair of an atrial septal defect, a ventricular septal defect or an atrioventricular septal defect

Exclusion Criteria:

1. Pulmonary artery or vein abnormalities being addressed surgically
2. Preoperative requirement for invasive mechanical ventilation or intravenous inotrope support
3. Any condition which, in the opinion of the investigator, might interfere with study objectives

Primary outcomes:
measure: L-citrulline Plasma Levels
timeFrame: Measured in seven blood sample time points from the beginning of surgery until end of IV Citrulline Infusion; at either 48 hours postoperatively or at extubation, whichever comes first.
Secondary outcomes:
measure: Postoperative Invasive Mechanical Ventilation (Mean and SD)
timeFrame: Measured in hours from the end of surgery until extubation, or Day 30, whichever occurs first
measure: Postoperative Invasive Mechanical Ventilation (Median and Range)
timeFrame: Measured in hours from the end of surgery until extubation or Day 30, whichever occurred first
measure: Total Duration of Respiratory Support
timeFrame: Baseline to discharge or Day 30, whichever occurs first
measure: Postoperative Intravenous Inotrope Duration
timeFrame: Measured at 48 hours
measure: Total Inotrope Score
timeFrame: PICU admission until Hour 48
measure: Time on Vasoactive Medications
timeFrame: Hour 0 to Hour 48
measure: Total Vasoactive Score
timeFrame: Hour 0 to Hour 48
measure: Length of ICU Stay
timeFrame: Measured in hours from the end of surgery to discharge from ICU or Day 30, whichever occurred first
measure: Composite Endpoint: Cessation of Positive Pressure Ventilation and of Inotrope Therapy
timeFrame: Until cessation of positive pressure ventilation and of inotrope therapy or Day 30, whichever occurred first
measure: Length of Hospitalization
timeFrame: Measured from the day of surgery until discharge from hospital or Day 30, whichever occurred first
measure: Incidence of Increased PVT (Defined as a Sustained Mean Pulmonary Artery Pressure Greater Than 20 mm Hg for at Least 2 Hours, Measured During the First 48 Hours
timeFrame: Measured in hours from the end of surgery until extubation or Day 30, whichever occurred first
measure: Duration of Chest Tube Drainage
timeFrame: Measured in hours from the end of surgery until removal of chest tubes or Day 30, whichever occurred first
measure: Volume of Chest Tube Drainage
timeFrame: Measured in milliliters from the end of surgery until removal of chest tubes or Day 30, whichever occurred first
measure: Survival
timeFrame: Measured at 28 days post surgical repair
measure: Number of Patients With Clinically Significant Hypotension.
timeFrame: Mean Arterial Blood pressure as continuously monitored postoperatively in the PCCU (Hour 0 to Hour 24) during Citrulline or Placebo infusion.
Other outcomes:
measure: Arginine Concentrations
timeFrame: Baseline to Hour 48
measure: Nitric Oxide Concentrations
timeFrame: Baseline to Hour 48
Locations:
city: Saint Louis
country: United States
facility: Washington University Children's Hospital
state: Missouri
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
Study officials:
affiliation: Batson Children's Hospital, University of Mississippi Medical Center
name: Frederick E Barr, MD
role: STUDY_CHAIR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Catherine Krawczeski, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Louis Children's Medical Center
name: Allan Doctor, MD
role: PRINCIPAL_INVESTIGATOR
References: