The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery

NCT ID: NCT02188576

Last Updated: 2020-01-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 66 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-08-31
• Study Completion Date: 2018-01-31

Brief 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.

Conditions

Craniosynostosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

high dose TXA

High dose TXA is the intervention.

A higher dose of tranexamic acid will be given to this arm as follows:

50 mg/kg loading dose and 5 mg/kg/h infusion

Group Type: EXPERIMENTAL

high dose TXA

Intervention Type: DRUG

Low Dose TXA

Low dose TXA is the intervention.

A lower dose of TXa will be given as follows:

10 mg/kg loading dose and 5 mg/kg/h infusion

Group Type: EXPERIMENTAL

Low dose TXA

Intervention Type: DRUG

Interventions

high dose TXA

Intervention Type: DRUG

Low dose TXA

Intervention Type: DRUG

Other Intervention Names

Tranexamic acid, Cyclokapron; Craniofacial surgery; Tranexamic Acid, cyclokapron,; Craniofacial surgery

Eligibility Criteria

Inclusion Criteria

• Patients (age range 3 months to 6 years) undergoing craniosynostosis repair, fronto-orbital advancement surgery and cranial remodeling surgery (i.e. total cavernal remodeling surgery).

Exclusion Criteria

• Preexisting hematological abnormality (defined as a positive history of bleeding disorder or a known diagnosis of a genetic or acquired bleeding disorder)
• Preexisting coagulation defect (defined as PT, PTT or INR >1.5 times normal or a n pre-existing genetic or acquired coagulation defect))
• Preexisting hepatic, renal, vascular, ocular and/or metabolic disorder
• History of acetylsalicylate ingestion within the last 14 days.
• History of NSAIDs ingestion with 2 days of the scheduled surgery date

• Minimum Eligible Age: 3 Months
• Maximum Eligible Age: 6 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Boston Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Susan Goobie

Senior Assistant in Perioperative Anesthesia

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Susan Goobie, MD

Role: PRINCIPAL_INVESTIGATOR

Boston Children's Hospital

Nicola Disma, MD

Role: PRINCIPAL_INVESTIGATOR

Gaslini Children's Hospital

Locations

Boston Children's Hospital

Boston, Massachusetts, United States

Countries

United States

References

Goobie SM, Staffa SJ, Meara JG, Proctor MR, Tumolo M, Cangemi G, Disma N. High-dose versus low-dose tranexamic acid for paediatric craniosynostosis surgery: a double-blind randomised controlled non-inferiority trial. Br J Anaesth. 2020 Sep;125(3):336-345. doi: 10.1016/j.bja.2020.05.054. Epub 2020 Jun 30.

Reference Type: DERIVED

PMID: 32620262 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

P00008434

Identifier Type: -

Identifier Source: org_study_id