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

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Brief Title

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

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.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

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.

Secondary Outcome

 Duration of postoperative mechanical ventilation in hours compared between treatment groups

Condition

Atrial Septal Defect

Intervention

Intravenous L-Citrulline

Study Arms / Comparison Groups

 Intravenous L-Citrulline
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

22

Start Date

September 2010

Completion Date

April 2012

Primary Completion Date

April 2012

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
      

Gender

All

Ages

N/A - 6 Years

Accepts Healthy Volunteers

No

Contacts

Frederick E Barr, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01120964

Organization ID

CIT-002-01


Responsible Party

Sponsor

Study Sponsor

Asklepion Pharmaceuticals, LLC


Study Sponsor

Frederick E Barr, MD, Study Chair, Batson Children's Hospital, University of Mississippi Medical Center


Verification Date

January 2015