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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Asklepion Pharmaceuticals, LLC
ClinicalTrials.gov Identifier:
NCT01120964
First received: May 6, 2010
Last updated: June 5, 2013
Last verified: June 2013
  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.

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.


Condition Intervention Phase
Atrial Septal Defect
Ventricular Septal Defect
Atrioventricular Septal Defect
Drug: Intravenous L-Citrulline
Drug: Placebo of Intravenous L-Citrulline
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Investigator)
Primary Purpose: Prevention
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

Resource links provided by NLM:


Further study details as provided by Asklepion Pharmaceuticals, LLC:

Primary Outcome Measures:
  • To determine if L-citrulline given perioperatively achieves a plasma citrulline level of > 100 umol/L in children undergoing surgical repair of an atrial septal defect, a ventricular septal defect or an atrioventricular septal defect. [ Time Frame: 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. ] [ Designated as safety issue: Yes ]
    Citrulline Blood Levels : 1. Baseline sample in OR prior to Cardiopulmonary Bypass prior to admistration of first bolus of Citrulline or Placebo 2. Immediately after Bolus 1 administered in Operating Room. 3. 30 minutes after separation from Cardiopulmonary Bypass; immediately prior to administration of Bolus 2 and start of continuous infusion of Citrulline or Placebo. 4. Six hours after after start of infusion. 5. 12 hours after start of infusion. 6. 24 hours after start of infusion. 7. 48 hours after start of infusion; or whenever infususion is discontinued if prior to 48 hours.


Secondary 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 ]
  • 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: Yes ]
  • 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 28 days post surgical repair ] [ Designated as safety issue: No ]
  • The incidence of clinically significant hypotension. [ Time Frame: Mean Arterial Blood pressure as continuously monitored postoperatively in the PCCU during Citrulline or Placebo infusion. ] [ Designated as safety issue: Yes ]
    Age specific mean aterial blood pressrue limits compared between the citrulline and placebo groups will be used to determine significant hypotension.


Enrollment: 22
Study Start Date: September 2010
Study Completion Date: April 2012
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Intravenous L-Citrulline Drug: Intravenous L-Citrulline
150mg bolus X 1 after initiation of cardiopulmonary bypass, the addition of L-citrulline at a concentration of 200 umol/L or placebo to the filtration and hemoconcentration fluid utilized during cardiopulmonary bypass in addition to a 20mg/kg bolus 30 minutes after separation from cardiopulmonary bypass immediately followed by a continuous infusion of 9mg/kg/hr IV, and ending at 48 hours continuous infusion or discharge from the PCCU.
Placebo Comparator: Placebo of Intravenous L-Citrulline Drug: Placebo of Intravenous L-Citrulline
Placebo of Intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug

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

Ages Eligible for Study:   up to 6 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01120964

Locations
United States, Missouri
Washington University Children's Hospital
St. Louis, Missouri, United States, 63110
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Sponsors and Collaborators
Asklepion Pharmaceuticals, LLC
Investigators
Study Chair: Frederick E Barr, MD Batson Children's Hospital, University of Mississippi Medical Center
Principal Investigator: Catherine Krawczeski, MD Children's Hospital Medical Center, Cincinnati
Principal Investigator: Allan Doctor, MD St. Louis Children's Medical Center
  More Information

No publications provided

Responsible Party: Asklepion Pharmaceuticals, LLC
ClinicalTrials.gov Identifier: NCT01120964     History of Changes
Other Study ID Numbers: CIT-002-01
Study First Received: May 6, 2010
Last Updated: June 5, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Additional relevant MeSH terms:
Heart Septal Defects
Heart Septal Defects, Atrial
Heart Septal Defects, Ventricular
Endocardial Cushion Defects
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Congenital Abnormalities

ClinicalTrials.gov processed this record on August 21, 2014