Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery : Revised Protocol

NCT ID: NCT01120964

Last Updated: 2022-07-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-09-30
• Study Completion Date: 2012-04-30

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.

Conditions

Atrial Septal Defect; Ventricular Septal Defect; Atrioventricular Septal Defect

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: SINGLE

Study Groups

Intravenous L-Citrulline

IV bolus of 150 mg/kg L-citrulline at the initiation of bypass, followed by L-citrulline (200 μmol/L) addition to the filtration or hemoconcentration replacement fluid used during bypass. Plus L-citrulline (20 mg/kg) bolus 30 minutes after decannulation from bypass, immediately followed by 9 mg/kg/h continuous L-citrulline infusion for 48 hours.

Group Type: EXPERIMENTAL

Intravenous L-Citrulline

Intervention Type: DRUG

Placebo of Intravenous L-Citrulline

Placebo administered according to the same schedule as L-citrulline

Group Type: PLACEBO_COMPARATOR

Placebo of Intravenous L-Citrulline

Intervention Type: DRUG

Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug

Interventions

Intravenous L-Citrulline

Intervention Type: DRUG

Placebo of Intravenous L-Citrulline

Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug

Intervention Type: DRUG

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

• Maximum Eligible Age: 6 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Asklepion Pharmaceuticals, LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Frederick E Barr, MD

Role: STUDY_CHAIR

Batson Children's Hospital, University of Mississippi Medical Center

Catherine Krawczeski, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital Medical Center, Cincinnati

Allan Doctor, MD

Role: PRINCIPAL_INVESTIGATOR

St. Louis Children's Medical Center

Locations

Washington University Children's Hospital

St Louis, Missouri, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Countries

United States

Other Identifiers

CIT-002-01

Identifier Type: -

Identifier Source: org_study_id