The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
Condition: Craniosynostosis
MeSH terms: Craniosynostoses
Study type: Interventional
Phase: Phase 4

Summary: 
      This research study is being performed to evaluate two different doses of Tranexamic acid
      (TXA) in children who have craniosynostosis and have been referred to Boston Children's
      Hospital for corrective surgery. This surgery is associated with significant blood loss and
      frequently requires the transfusion of blood. TXA is a medication that reduces the amount of
      bleeding during surgery by improving clotting of the blood at the surgical site. TXA is an
      FDA-approved drug that is routinely used in infants and children undergoing major surgery
      including heart surgery, craniofacial surgery and scoliosis surgery. It has been shown to
      decrease both the amount of bleeding and the amount of blood transfusion needed. We would
      like to compare the different doses of TXA to see if a lower dose has the same effect on
      blood loss as a higher dose. We are also interested to learn why TXA seems to work better in
      some patients than in others. In order to study the effect of this drug we would like to give
      this drug to your child and measure the blood loss and the volume of blood given to your
      child during his/her surgery.

      The research is being done at two sites; Boston Children's Hospital and Gaslini Children's
      Hospital in Genoa, Italy. The main study doctor from Boston Children's Hospital is Dr. Susan
      Goobie. The Department of Anesthesiology at Boston Children's Hospital is sponsoring this
      study.

      We are planning to study a total of 68 infants and children from age 3 months to 6 years old
      scheduled for open craniosynostosis surgery at Boston Children's Hospital or Gaslini
      Children's Hospital.
    

Detailed description: 
      Introduction: Over 90% of open craniosynostosis surgical procedures are associated with a
      transfusion of blood or blood products. Goobie et. al. recently showed that tranexamic acid
      in a dose of 50 mg/kg/15min and 5 mg/kg/h significantly reduced blood loss and transfusion
      requirements as well as the overall exposure of children to donor PRBC by two thirds.
      However, using a moderately high dosing regimen, TXA plasma concentrations were shown to far
      exceed the accepted therapeutic level (by over 10 fold). No side effects of TXA were found in
      this study but a recent study suggests that currently recommended high to moderate TXA dosing
      regimens are potentially associated with neurological complications in children. Goobie et.
      al. developed a population pharmacokinetic model of TXA and simulated a dose response curve
      for this population. From this model and simulation, it appears that reducing the loading
      dose to 10 mg/kg/15 min followed by a 5 mg/kg/h infusion is adequate to maintain plasma
      concentrations above the accepted therapeutic level of 20ug/mL.

      It is important to test and validate this reduced dosage scheme in a multicenter study. The
      hypothesis is that this reduced dosage scheme (10 mg/kg loading dose and 5 ug/kg/h) is as
      effective as the higher dosage scheme (50 mg/kg loading dose and 5 mg/kg/h) in decreasing
      blood loss and transfusion requirements in children undergoing open craniosynostosis surgery.
      Thus the PK/PD profile of TXA in craniosynostosis patients will be determined with genomics
      explored as a cause of interpatient variability in the response to tranexamic acid.

      Experimental Design: With IRB approval and informed consent 68 pediatric patients aged 3 m to
      6 years coming for open craniofacial surgery will be randomized in a prospective double blind
      fashion to either the current standard intravenous TXA dose (50mg/kg/15min and 5 mg/kg/h) or
      this lower TXA dose (10 mg/kg/15min and 5 mg/kg/h) until the end of surgery. A standardized
      anesthetic and well defined fluid, blood and blood product management protocols will be
      followed with improved modifications from the previously described protocol.

      Data Analysis Plan: A preliminary power analysis indicated that a total sample size of 56
      children (28 in randomized each group) would provide 80% statistical power to test whether
      the difference in average blood loss is equivalent to within 25% (ie 15 cc/kg) assuming a
      standard deviation of 30% ie +/- 22 ml/kg (moderate effect size = 0.68) . We plan to
      randomize 68 patients; 34 per group to ensure that we meet our sample size requirements while
      accounting for a potential 20% patient drop out.

      Specific Aims:

        1. Determine the efficacy of TXA (PD) in infants and children undergoing open craniofacial
           surgery with this lower dosage scheme.

        2. Determine the population pharmacokinetics (PK) of TXA in infants and children undergoing
           open craniofacial surgery with this dosage scheme.

        3. Determine the influence of genetics on response to TXA.

        4. Attempt to better define efficacy of TXA in a direct manner using a novel and innovative
           approach by obtaining pre and post biological markers of fibrinolysis (as bleeding and
           blood loss are difficult to measure accurately and are an indirect measure of TXA
           efficacy of inhibition of fibrinolysis.
    

Intervention name(s): high dose TXA; Low dose TXA
Intervention type(s): Drug; Drug
Other intervention name(s): Tranexamic acid, Cyclokapron; Craniofacial surgery; Tranexamic Acid, cyclokapron,; Craniofacial surgery
Intervention MeSH terms: Tranexamic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Craniofacial Surgery; tranexamic acid; Antifibrinolytic