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Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery

This study has been completed.
Sponsor:
Collaborator:
Vanderbilt University
Information provided by:
Asklepion Pharmaceuticals, LLC
ClinicalTrials.gov Identifier:
NCT00335244
First received: June 7, 2006
Last updated: January 19, 2010
Last verified: January 2010
History of Changes
  Purpose

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.


Condition Intervention Phase
Heart Defects, Congenital
Hypertension, Pulmonary
 Drug: L-citrulline
Drug: Placebo of intravenous L-citrulline
 Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Phase III Double Blind, Randomized, Placebo Controlled, Clinical Trial to Determine the Safety and Efficacy of Intravenous L-Citrulline Versus Placebo in Children Undergoing Cardiopulmonary Bypass

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Asklepion Pharmaceuticals, LLC:

Primary Outcome Measures:
  • Duration of postoperative mechanical ventilation in hours compared between treatment groups. [ Time Frame: Measured in hours from the end of surgery until extubation ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 [ Time Frame: Measured in hours from the end of surgery until extubation ] [ Designated as safety issue: Yes ]
  • Postoperative intravenous inotrope score [ Time Frame: Measured at 48 hours ] [ Designated as safety issue: No ]
  • Length and volume of chest tube drainage [ Time Frame: Measured in hours from the end of surgery until removal of chest tubes ] [ Designated as safety issue: No ]
  • Length of ICU stay [ Time Frame: Measured in hours from the end of surgery to discharge from ICU ] [ Designated as safety issue: No ]
  • Length of hospitalization [ Time Frame: Measured from the day of surgery until discharge from hospital ] [ Designated as safety issue: No ]
  • Survival [ Time Frame: Measured at 30 days post surgical repair ] [ Designated as safety issue: No ]

Enrollment: 77
Study Start Date: May 2006
Study Completion Date: December 2009
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Intravenous L-citrulline
 Drug: L-citrulline
150mg bolus X 1 after initiation of cardiopulmonary bypass followed by continuous infusion of 9mg/kg/hr IV, starting 4 hours post bolus administration and ending at 48 hours continuous infusion or discharge from the PCCU
Placebo Comparator: 2
Placebo of intravenous L-citrulline
 Drug: Placebo of intravenous L-citrulline
Placebo of intravenous L-citrulline

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. The hypothesis is that genetic polymorphisms in the rate limiting urea cycle enzyme CPSl, and other important enzymes in the urea cycle, influence the availability of NO precursors. It is further 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

Ages Eligible for Study:   up to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Undergoing cardiopulmonary bypass surgery with 1 of the following 5 procedures:

    1. AVSD repair
    2. VSD repair
    3. Bidirectional Glenn
    4. Modified Fontan
    5. Arterial switch

Exclusion Criteria:

  • Pulmonary artery or vein abnormalities not being addressed surgically
  • Preoperative requirement for mechanical ventilation or intravenous inotrope support
  • Any condition that might interfere with study objectives, as determined by the investigator
  • Pregnant
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00335244

Locations
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Asklepion Pharmaceuticals, LLC
Vanderbilt University
Investigators
Principal Investigator: Fredrick E. Barr, MD, MSCI Vanderbilt University
  More Information

No publications provided

Responsible Party: Gary R. Pasternack, MD, PHD, Interim CEO, Asklepion Pharmaceuticals, LLC
ClinicalTrials.gov Identifier: NCT00335244     History of Changes
Other Study ID Numbers: 409, R01 HL73317-01, IRB# 060197
Study First Received: June 7, 2006
Last Updated: January 19, 2010
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Congenital Abnormalities
Heart Defects, Congenital
Hypertension
Hypertension, Pulmonary
Cardiovascular Abnormalities
 Cardiovascular Diseases
Heart Diseases
Vascular Diseases
Lung Diseases
Respiratory Tract Diseases

ClinicalTrials.gov processed this record on October 16, 2012