Clinical trial NCT02188576
Conditions: Craniosynostosis
Keywords: Craniofacial Surgery tranexamic acid Antifibrinolytic
Sponsor: Boston Children's Hospital
Start date: 2014-08-01; Completion date: 2018-01-01
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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 arm 2: 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
Interventions: intervention 1: high dose TXA intervention 2: Low dose TXA
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Efficacy of High and Low Dose Tranexamic Acid Dosage Regimes for 
Craniosynostosis Surgery; A Randomized Controlled Non-Inferiority 
Multicenter Trial. 
Document date: June 3, 2019 
Submitted to ClinicalTrials.gov : November 20, 2019 
NCT identifier: NCT02188576 
Manuscript in submitted for publication Nov 2019. 
Key words: tranexamic acid, antifibrinolytics, craniosynostosis, pediatrics, bleeding, blood loss, blood 
transfusion. 
What is already known: Tranexamic acid is efficacious at decreasing blood loss and blood transfusion in 
pediatric craniosynostosis surgery. 
What this article adds: A tranexamic acid dose regimen of 10 mg/kg loading dose and 5 mg/kg/h 
maintenance dose is as effective as a higher dose regime of 50 mg/kg loading dose and 5 mg/kg/h 
maintenance infusion rate in reducing blood loss and transfusion requirements in pediatric craniosynostosis 
reconstruction surgery. 
 
 
EXPERIMENTAL DESIGN AND METHODS:  
With Internal Research Board and Ethics board approval from the two participating hospitals: 
(BCH IRB-P00008434) and (GCH Ethic 2013-001056-35) and with informed consent, 68 pediatric 
patients aged 3 months to 6 years scheduled for open craniofacial surgery were randomized in a 
prospective double-blind fashion to either the current standard intravenous TXA dose 
(50mg/kg/15 min and 5 mg/kg/h) or a lower TXA dose (10 mg/kg/15 min and 5 mg/kg/h) until 
the end of surgery (ClinicalTrials.gov identifier: NCT02188576). A standardized anesthetic and 
well-defined fluid, blood and blood product management/ transfusion protocol was followed 
with improved modifications (regarding patient blood management guidelines) from our 
previously described protocol. CONSORT guidelines for randomized trials were followed. 
Patients (age range 3 months to 6 years) undergoing craniosynostosis repair consisting of open 
cranial remodeling surgery were included (including fronto-orbital advancement surgery, 
posterior and total calvernal remodeling procedures). Exclusion criteria were patients with a 
pre-existing active hematological abnormality (defined as a known diagnosis of an active genetic 
or acquired bleeding disorder/coagulation defect), pre-existing current coagulation defect 
(defined as screening PT, PTT or INR >1.5 times normal), or acetylsalicylate ingestion within the 
last 4 days or nonsteroidal anti-inflammatory ingestion with 2 days of the scheduled surgery 
date. Subjects were recruited in the preoperative clinic by the anesthesia research nurse and, 
with informed parental and patient consent, were randomly assigned to receive either 


intravenous TXA or 0.9% normal saline, according to an investigator blinded computer 
generated random number sequence 
Preoperative data collected included: age, weight, height, gender, race, coexisting diseases, 
cranial suture(s) involved, preoperative hemoglobin, hematocrit, platelets, PT, PTT, and INR, 
fibrinogen and blood group. Intraoperative data collected included: estimated volume of blood 
lost as calculated using the previously validated formula: ERCVlost = ERCVpreop +  
ERCVtransfused -  ERCVpostop  (ERCV = Estimated Red Cell Volume)(6) , total surgical time 
(defined as from incision to last stitch), amount and type of crystalloid and colloid agents 
administered intravenously, blood product transfusion requirements in the operating room  
(both total volume and number of exposed units; packed red blood cell, fresh frozen plasma,  
platelet concentrates, and cryoprecipitate), and total urine output. 
Laboratory data was collected at the following times: after arterial line placement for baseline 
measurements, prior to intraoperative blood product transfusion, at the end of surgery prior to 
transport from the operating room to the Intensive Care Unit and 24 hours postoperatively and 
consisted of arterial blood gas, hemoglobin, hematocrit, platelet count, PT, PTT and INR, 
fibrinogen and d-dimer levels and other biological markers . 
Postoperative data collection included surgical drain output, blood transfusion and the 
occurrence of any postoperative complications.  Patients were visited postoperatively daily 
while in the hospital and a follow-up phone call was made to the family once the patient 
returned home within 6 months of surgery. These postoperative follow-ups focused on 
identifying any complications or side effects with specific attention to thromboembolic and 
neurological side effects. 
 
Statistical Analysis Plan 
An a priori power analysis indicated that a total sample size of 56 children (28 in randomized 
each group) would provide 80% statistical power ( = 0.05, = 0.20) to test whether the 
difference in average blood loss is equivalent to within 20 mL/kg assuming a standard deviation 
of 30% (moderate effect size = 0.68) (version 7.0, nQuery Advisor, Statistical Solutions, Saugus, 
MA). Sixty-eight patients were randomized; 34 per group to ensure sample size requirements 
were met while accounting for a potential 20% patient drop out. A single randomization list for 
was used for both sites; BCH and GCH with stratification per site. 
The low dosage and high dosage groups are compared with respect to demographics, baseline 
characteristics, lab values, and intraoperative and postoperative outcomes. Continuous data are 
presented as mean and standard error or median and interquartile range with comparisons 
performed using Student’s t-test or the Wilcoxon rank sum test as appropriate. Medians and 
interquartile ranges are presented where the data deviate from normality, including age, 
weight, length of stay, blood loss and PRBC transfused.  Categorical data are presented as 
frequency and percentage with comparisons made by Fisher’s exact test. Mean differences 


between the two dosage groups are presented with 95% confidence intervals. For data 
presented with median and interquartile range, a 95% confidence interval estimate for the 
difference between comparison groups was obtained using 1000 bootstrap resamples.  
Statistical analyses was performed using Stata (version 15.0, StataCorp, College Station, TX). A 
two-sided alpha of 0.05 was used to determine statistical significance.