Clinical trial NCT03287336
Conditions: Postpartum Hemorrhage
Keywords: tranexamic acid postpartum hemorrhage
Sponsor: George Washington University
Start date: 2018-01-02; Completion date: 2023-09-30
Enrollment: 43 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Postpartum hemorrhage is a significant contributor to maternal morbidity and mortality and is worldwide. TXA has recently been proven to reduce mortality when given to women in setting of diagnosed PPH. US obstetricians and anesthesiologists are hesitant to use TXA in the peripartum period especially for prevention of PPH due to uncertainty of an optimal dose and safety profile. The purpose of this study is to characterize the pharmacokinetics of TXA when given prophylactically at time of delivery. In addition investigators will determine the pharmacodynamics of TXA in the peripartum period.

Detailed description:
Conduct a prospective, open-label, dose finding PK study in 30 pregnant 3rd trimester women scheduled for non-emergent cesarean section who are at risk for hemorrhage. Three doses of the drug will be administered in an escalating fashion by cohort with the lowest dose first. A maximum of 1 gram will be administered. TXA serum levels at several time points after delivery will be assayed. A PK model will be constructed for determining the optimal TXA dose administered at parturition.

Arms: arm 1: Dose of Tranexamic acid 5mg/kg will be administered. arm 2: Dose of Tranexamic acid 10 mg/kg will be administered. arm 3: Dose of Tranexamic acid 15 mg/kg will be administered.
Interventions: intervention 1: Tranexamic Acid
Intervention descriptions: intervention 1: Tranexamic acid dosage (5 mg/kg, 10 mg/kg and 15 mg/kg) administered in a dose escalating fashion by cohort with the lowest dose first.

Protocol documents:
ICF_002.pdf: 
IRB Number and Approval Date (OHR Staff Only)
 
Page 1 of 7
BioMed Informed Consent (HRP-500)
Consent Version Date:   - December 26, 2018
GW OHR Document Revision Date: 16DEC16
Informed Consent for Participation in a Research Study 
Title of Research Study: Prevention of postpartum hemorrhage (bleeding):  pharmacokinetics 
and pharmacodynamics of Tranexamic Acid
Investigator: Dr. Homa Ahmadzia
Investigator Contact Information:
 
Phone:  202-741-2500
Email:  hahmadzia@mfa.gwu.edu
Why am I being invited to take part in a research study?
We invite you to take part in a research study because you are having a Cesarean section at the 
George Washington University Hospital and have been identified at risk for bleeding after delivery 
What should I know about a research study?
 
Someone will explain this research study to you. You may ask all the questions you want 
before you decide whether to participate.

Participation is voluntary; whether or not you take part is up to you.  

You can agree to take part and later change your mind.

Your decision not to take part or to stop your participation will not be held against you.

Your decision will not affect the medical care you receive from GW. If you decide not to take 
part, you can still receive medical care from GW.

You may take this document home to read or to discuss with your family members or doctor 
before deciding to take part in this research study.
ClinicalTrials.gov is a website that provides information about federally and privately supported 
clinical trials. A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This website will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this website at any time.
Who can I talk to if I have questions?
If you have questions, concerns, or complaints, or think the research has hurt you, talk to the Principal 
Investigator at 202-741-2500.
This research is being overseen by an Institutional Review Board (“IRB”). You may talk to them at 
202-994-2715 or via email at ohrirb@gwu.edu if:

You have questions, concerns, or complaints that are not being answered by the research 
team or if you wish to talk to someone independent of the research team.

You have questions about your rights as a research subject.
IRB NUMBER: 041737
IRB APPROVAL DATE: 02/06/2019


IRB Number and Approval Date (OHR Staff Only)
Informed Consent for Participation in a Research Study
Page 2 of 7
BioMed Informed Consent (HRP-500)
Consent Version Date:  December 26, 2018 
GW OHR Document Revision Date: 16DEC16
Why is this research being done?
After delivery bleeding causes significant problems for mothers after delivery and is worldwide 
responsible for approximately 10 maternal deaths every hour. Prediction for who is at risk for severe 
bleeding is not reliable based on current methods. Aside from medications that help the uterus 
decrease in size for treatment and/or prevention, few other simple medical solutions exist.
Tranexamic acid (TXA) is an inexpensive and easy to administer drug that prevents blood clots from 
breaking down, routinely used in cardiac, trauma and orthopedic patients to prevent bleeding and 
reduce deaths. Most of the evidence to support dosing recommendations for clinical studies are 
based on drug level data from non-pregnant patients. High dose exposure to TXA among non-
pregnant patients is associated with stomach side effects, seizures and a potential increase in blood 
clotting risk. Thus, US obstetricians and anesthesiologists are less likely to use TXA around delivery 
for prevention of after delivery bleeding due to uncertainty about the best dose to prevent bleeding 
and limit side effects.
The purpose of this study is to find out about drug levels of TXA when given for prevention at time of 
delivery. Three doses will be tested, (5, 10 and 15mg/kg). There is no standard dose; in previous 
studies using pregnant women the standard dose often ranges from 10-15mg/kg. 
In addition, we aim to determine the impact TXA has on your blood taken in the period after delivery. 
This will involve some bleeding/clotting tests to be performed in the laboratory. This research may 
provide a method to make a common and necessary procedure safer and potentially reduce your risk 
for the need to receive a blood transfusion. 
How long will I be in the study?
We expect that you will be in this research study for approximately 6 weeks, from the time you 
consent to the study until 6 weeks after your Cesarean section.   
How many people will take part in this research study?
We expect 45 participants to take part in the entire study.
What happens if I agree to be in this research?
If you agree to take part in this research, the following study procedures will take place:
1.
You will be asked to review and sign the study’s consent form.  This form also contains a 
HIPAA authorization permitting us to access your medical records as necessary to the study.
2.
You will be assigned to one of the following three groups to determine what dosage of TXA 
you will be given at your scheduled Cesarean section: 
a.
Participants in Group 1 will receive 5 mg/kg of TXA
b.
Participants in Group 2 will receive 10 mg/kg of TXA, up to a maximum dose of 1 gram
c.
Participants in Group 3 will receive 15 mg/kg of TXA, up to a maximum dose of 1 gram
3.
On the day of your scheduled Cesarean section, you will receive your assigned dosage of TXA 
after the baby has been delivered. If recommended by your physician, a blood sample will be 
collected prior to delivery to measure your kidney function.
4.
The amount of estimated blood loss (EBL) or total bleeding during and after delivery will be 
calculated.  
IRB NUMBER: 041737
IRB APPROVAL DATE: 02/06/2019


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Informed Consent for Participation in a Research Study
Page 3 of 7
BioMed Informed Consent (HRP-500)
Consent Version Date:  December 26, 2018 
GW OHR Document Revision Date: 16DEC16
5.
Six blood samples will be taken in the first 8 hours and one taken at 24 hours after drug 
administration to determine the effect of the study drug. A second IV will be placed in one of 
your veins, in order for these blood samples to be collected. We will most likely collect this 
from the intravenous tubing you will have already in place.
Breast milk samples will be taken after feedings during the after delivery hospital stay when is 
convenient for you after feeding the baby. A very small amount (<2ml) sample will be obtained 
2-4 times in total. This can be obtained via breast pump or self-expression. 
6.
You will be evaluated during your hospital stay as well as by phone 1-2 weeks after delivery, 
and in person at 6 weeks for any signs or symptoms related to blood clots. We will ask about 
the health of your baby during these evaluations. 
If you take part in this research, you will be responsible for fully understanding the study prior to 
agreeing to participate.  There will be no additional visits taking place outside of the scheduled time 
for your Cesarean section, so you will not be responsible for returning to the clinic for follow up visits 
outside of the normal care.
What other choices do I have besides taking part in the research?
An alternative to participating in the study is to not participate.  All persons approached for this study 
will receive the same level of high quality care regardless of whether they choose to participate.
What happens if I agree to be in research, but later change my mind?
You may refuse to participate or you may discontinue your participation at any time without penalty or 
loss of benefits to which you would otherwise be entitled.
If you decide to leave the research, contact the investigator so that the investigator can ensure no 
additional study procedures occur.  To formally rescind your consent to participate, you must put this 
request in writing.  You may do so by either emailing Dr. Homa Ahmadzia at 
hahmadzia@mfa.gwu.edu or you may write a letter and send it to:  
Dr. Homa Ahmadzia, MD-MPH
2150 Pennsylvania Ave. NW Suite 6A Washington DC, 20037
If you stop being in the research, already collected data may not be removed from the study 
database. You will be asked whether the investigator can collect data from your routine medical care. 
If you agree, this data will be handled the same as research data. 
What determines my eligibility to participate in this study?
Participants are pre-selected for the study if they meet the following eligibility criteria:
Inclusion Criteria: 
a.
Women who are undergoing medically indicated cesarean section  at greater than 34+0 weeks 
gestation or women undergoing elective cesarean section at 39+0 weeks gestation in 
accordance with recommendations from the American Congress of Obstetricians and 
Gynecologists
b.
Women who are undergoing elective or non-urgent cesarean delivery greater than 34+0 weeks 
gestation.
c.
Pregnant women with normal kidney function
IRB NUMBER: 041737
IRB APPROVAL DATE: 02/06/2019


IRB Number and Approval Date (OHR Staff Only)
Informed Consent for Participation in a Research Study
Page 4 of 7
BioMed Informed Consent (HRP-500)
Consent Version Date:  December 26, 2018 
GW OHR Document Revision Date: 16DEC16
A patient will not be asked to participate in this study if they are found to have one or more of the 
following non-eligibility criteria:
Exclusion criteria:  
a.
Patients younger than 18 or older than 50
b.
women with active blood clot or blood clotting disease
c.
Women with a history of blood clot
d.
Women with blood clotting problem or a medical condition that makes them more likely to have a 
blood clotting problem (i.e. lupus, antiphospholipid syndrome)
e.
Women with a brain bleed
f.
Women with acquired defective color vision (problem with seeing certain colors)
g.
history of seizure disorder
h.
known kidney problems (serum creatinine >0.9)
i.
Twin or triplet pregnancies
j.
Abnormal over-reaction to Tranexamic acid or similar medications
k.
History of known liver problems
Is there any way being in this study could be bad for me?
Possible risks and discomforts you could experience during this study include:

Psychological:  you may experience emotional discomfort if you are worried that a different 
level of care will be given to those who do or do not participate in this study.   However, all 
efforts will be made to assure patients that participation in this study will not affect the quality 
of care received. 

Privacy: There is also a risk of breach of your private medical information. All efforts will be 
made to ensure that private medical information is protected. Risk of breach of privacy will be 
minimized by undertaking both recruitment and consent in the clinic and hospital, at your 
appointment in a private office or exam room. The research coordinator and the clinicians will 
practice discretion in choosing when to discuss the patient’s involvement in the study.  
Furthermore, all patients who participate in the study will receive a special study number, and 
any study data collected will be labeled with that patient’s special study number and stored in 
secure password protected digital locations.  The only connection between your name and 
your special study number will be a code log.  This log will be stored in a locked file cabinet in 
the research coordinator’s locked office at the MFA, separate from any other documents 
relating to this study.
Physical:  Risks of tranexamic acid include nausea, vomiting, diarrhea, seizures, and an allergic 
reaction. Tranexamic acid has been studied in a broad range of surgical and obstetrics studies and 
the risk for blood clots in the veins is thought possible but has not actually been shown. In the small 
randomized trials thus far in obstetric literature, there is no increased risk for blood clots found. Your 
baby will be exposed to the study drug. There may be other risks associated with this drug not yet 
known/published.  Participants will be immediately unenrolled from the study under the following 
conditions:
Subject Discontinuation Criteria:  
Women who experience any serious adverse side effect such as
a.
unknown drug reaction or sensitivity
b.
hives
c.
severe trouble breathing 
IRB NUMBER: 041737
IRB APPROVAL DATE: 02/06/2019


IRB Number and Approval Date (OHR Staff Only)
Informed Consent for Participation in a Research Study
Page 5 of 7
BioMed Informed Consent (HRP-500)
Consent Version Date:  December 26, 2018 
GW OHR Document Revision Date: 16DEC16
d.
swelling in face or 
e.
sudden blood clot,
while undergoing TXA infusion will be removed from the study and the infusion of study drug will be 
stopped immediately.  There is no optimal dose in pregnancy and that is why we are doing the 
study.  The doses will be given in increasing fashion, meaning that participants enrolling early in the 
study will be given relatively low doses of the study drug and participants enrolling later will receive 
higher doses. Your assignment to a group is based on when you join the study rather than a medical 
decision made by the research team. The maximum dose being studied in this study is equal to the 
maximum dose being used in another large study using this drug for prevention where they plan to 
include 4,000 pregnant women.
Tranexamic acid is an FDA approved Category B drug, which means that it is not thought to harm the 
fetus. In this study, your baby will be exposed to TXA just before birth and TXA may transfer into 
breast milk in much smaller amounts.  The effects of TXA in breast milk are currently unknown but to 
date there has been no evidence of harm to the newborn. 
You and your insurance company will be charged for the health care services that you would 
ordinarily be responsible to pay. In some cases, insurance will not pay for services ordinarily covered 
because these services were performed in a research study. You should check with your insurance to 
see what services will be covered by your insurance and what you will be responsible to pay.
What happens if I believe I am injured because I took part in this study?
The researchers have taken steps to minimize the known or expected risks. In spite of all precautions, 
you still may experience medical complications or side effects from participating in this study. You 
should promptly notify the study doctor in the event of any illness or injury as a result of being in the 
study.
If you believe that you have been injured or have become ill from taking part in this study, you should 
seek medical treatment from GWU Hospital and/or the GWU MFA or through your physician or 
treatment center of choice. Care for such injuries will be billed in the ordinary manner to you or your 
insurance company. 
You will not receive any financial payments from GWU, GWU Hospital and/or the GWU MFA for any 
injuries or illnesses. You do not waive any liability rights for personal injury by signing this form.
Will being in this study help me in any way?
We cannot promise any benefits to you or others from your taking part in this research. However, 
possible benefits include decreased complications, decreased need for blood transfusions, and faster 
recovery if tranexamic acid does minimize blood loss during cesarean section. Additionally, as many 
patients with cesarean sections may get repeat operations for delivery during their lifetime, results of 
this study may inform management of repeat cesarean sections in the future.
The potential indirect benefits of the study are also significant. This research may provide a method to 
make a common and necessary procedure safer. It may potentially help future studies designed to 
identify the lowest safest dose for women to use during childbirth for prevention of after delivery 
bleeding.
Can I be removed from the research without my permission?
The person in charge of the research study or the sponsor can remove you from the research study 
without your approval. Possible reasons for removal include a change in your medical history between 
IRB NUMBER: 041737
IRB APPROVAL DATE: 02/06/2019


IRB Number and Approval Date (OHR Staff Only)
Informed Consent for Participation in a Research Study
Page 6 of 7
BioMed Informed Consent (HRP-500)
Consent Version Date:  December 26, 2018 
GW OHR Document Revision Date: 16DEC16
the time you agree to participate and when you are scheduled for your scheduled cesarean section 
which, in the opinion of the investigator, no longer makes you a good candidate for our study. We will 
tell you about any new information that may affect your health, welfare, or choice to stay in the 
research.
What happens to my information collected for the research?
To the extent allowed by law, we limit your personal information to people who have to review it. We 
cannot promise complete secrecy. The IRB and other representatives of this organization may inspect 
and copy your information. Others include the Food and Drug Administration (FDA), and the 
Department of Health and Human Services (DHHS).
The sponsor, monitors, auditors, the IRB, the Food and Drug Administration will be granted direct 
access to your medical records to conduct and oversee the research. By signing this document you 
are authorizing this access. We may publish the results of this research. However, we will keep your 
name and other identifying information confidential.
How will my privacy and health information be protected?
The Health Insurance Portability and Accountability Act (HIPAA) requires that researchers and health 
care providers protect the privacy of information that identifies you and relates to your past, present 
and future physical and mental health or conditions, or the provision of health care. If you agree to 
participate in this research, protected health information will be used and shared with others for 
purposes of the study. Below is more detailed information about how your health information will be 
shared and protected.  By signing this form, you are allowing the people and groups that are listed in 
the next paragraphs to use your health information for this research study.  Your information will only 
be used or shared as explained in this authorization form
The use and release of protected health information is for the purpose of collecting data for this study.
Protected Health Information to be shared with researchers for the purposes of this study:  email and 
phone number (for recruitment purposes only), name, medical record number, age, date(s) of medical 
procedures, race/ethnicity, gender, blood samples (for lab analysis). 
Who may disclose your protected health information:  The researcher and the other members of the 
research team may obtain your individual health information from: 
Hospitals: The George Washington University Hospital
Clinics: The Medical Faculty Associates
And from hospitals, clinics, health care providers, and health plans that provide health care to you 
during the study.
By signing this form, you allow the use, sharing, copying, and release of your protected health 
information in connection with this study by:
•
The members of the research team;
•
Other healthcare providers such as labs which are part of the study;
•
Institutional officials who are responsible for compliance; Some of the tests in this study would 
have been done as part of your regular care.  These test results will be used both to treat you and to 
complete this research.  The test results will be recorded in your medical record. These study results 
will be included in your medical record.  Results of tests and studies done solely for this research 
study and not as part of your regular care will not be included in your medical record.
IRB NUMBER: 041737
IRB APPROVAL DATE: 02/06/2019


IRB Number and Approval Date (OHR Staff Only)
Informed Consent for Participation in a Research Study
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GW OHR Document Revision Date: 16DEC16
Once your health information has been disclosed to others outside of the hospitals and medical 
practices by your authorization or communication, the information may no longer be covered by the 
federal regulation that protects privacy of health information.    
Not signing this form or later canceling your permission will not affect your health care treatment 
outside the study, payment for health care from a health plan, or ability to get health plan benefits. 
However, if you do not give permission to use your health information, you may not take part in this 
study because your health information is needed in order to conduct this study.
This Authorization does not have an expiration date.  
However, you may cancel this authorization at any time.  Even if you cancel this authorization, the 
researchers may still use the protected health information they already have about you; however, no 
new health information or new biological specimens will be collected from you after you cancel your 
permission.
To cancel your permission, you will need to send a letter to Dr. Homa Ahmadzia stating that you are 
canceling your authorization. This letter must be signed and dated and sent to this address:
Homa Ahmadzia
2150 Pennsylvania Ave NW
Suite 6A
Washington DC, 20037
Are there any costs for participating in this research? 
There is no cost to you for participating in this research study.
Will I be paid for my participation in this research? 
If you agree to take part in this research study, we will pay you $200 in the form of a Visa gift card or 
instead of the gift card you will receive a Medela breast pump valued at $250 for your time and effort. 
You will receive this compensation after you have undergone delivery and all blood samples are 
collected.
What else do I need to know?
This research is being funded in part by GWU School of Medicine and Health Sciences. Results of 
this study will be made publicly available on www.clinicaltrials.gov.  
By signing below, you agree that the above information has been explained to you and you have had 
the opportunity to ask questions. You understand that you may ask questions about any aspect of this 
research during the course of the study and in the future. Your signature documents your permission 
to take part in this research. Your signature documents your permission to take part in this research.
_______________________________
Printed name of subject
 _______________________________
____________
Signature of subject
Date
________________________________
____________
Signature of person obtaining consent
Date
IRB NUMBER: 041737
IRB APPROVAL DATE: 02/06/2019

Prot_004.pdf: 

















SAP_005.pdf: 
Prevention of Postpartum Hemorrhage With Tranexamic Acid
 
 
 
          10/27/2023
              
 
       NCT#03287336


Statistical Analysis Plan 
Study Population 
This was a prospective, single-center, open-label, dose-ranging study that recruited thirty 
pregnant women at The George Washington University from February 2018 to May 2019. 
Inclusion criteria were normal renal function (serum creatinine < 0.9 mg/dL), and greater than 34
+0 weeks gestation age with planned cesarean delivery. Patients were excluded if they had a 
thromboembolic history or hypersensitivity to TXA (or any antifibrinolytic therapies). The study 
protocol was approved by the institutional review board (IRB# 041737), and written consent was 
obtained from each patient before entering the study.  
Dosing and Blood Sampling 
Thirty patients were treated sequentially: the first ten patients received 5 mg/kg of TXA, the 
second ten received 10 mg/kg of TXA, and the last ten received 15 mg/kg of TXA. Total body 
weight was used to calculate the actual doses, which were capped at 1000 mg. TXA 
(Cyklokapron®) was given intravenously at the time of umbilical cord clamping and was infused 
via an infusion pump for approximately 15 minutes (500 mL/hour of 110 mL volume).  
Maternal blood samples were collected from the opposite arm of drug administration through 
peripheral venous catheters or separate venous blood draws. Three samples per patient were 
taken at each sample time, including pre-drug, 10 minutes, 30-60 minutes, 1.5-3 hours, 4-6 
hours, 7-8 hours, and 24 hours post end-of-infusion. One of the three samples for PK analysis 
was drawn into a tube containing potassium ethylenediaminetetraacetic acid (Becton Dickinson 
Vacutainer tubes, K2 EDTA 7·2 mg). This sample was further centrifuged at 3000 xg for 15 
minutes to obtain platelet-poor plasma. The other two samples for PD analysis were drawn into 
tubes coated with sodium citrate (Becton Dickinson Vacutainer tubes, Na Citrate 0·109 M, 
3·2%). Samples were stored on dry ice until further analysis.  
Biomarkers and covariates 
TXA concentration determined by ultra-high-performance liquid chromatography-tandem mass 
spectrometry was used as the PK metric. A modified rotational thromboelastometry (ROTEM) 
analysis9 was used to quantify the anti-fibrinolysis effect of TXA. Maximum lysis (ML), the 
proportion of clot lysed from the maximum clot (range 0-100%), was chosen as the PD marker to 


reflect the lysis potential of a formed clot.10 Briefly, clotting was initiated with tissue factor and 
recalcification in the presence of exogenous recombinant tissue plasminogen activator, as 
described.11 The bioanalysis details regarding TXA concentration and ML measurements are 
published elsewhere.11  
Patient-specific routine clinical data were obtained from the electronic medical record. 
Demographic data included age, height, weight, and BMI. Pre-delivery laboratory data included 
serum creatinine level (Scr), platelet count, and hematocrit level. Cockcroft-Gault12 equation was 
used to estimate creatinine clearance (CrCl). Patient comorbidities (diabetes and hypertension) 
were also recorded.  
Data Analysis 
The population approach was adopted using Pumas v1.0.5 (www.pumas.ai).13 Non-linear mixed 
effects modeling with first-order conditional estimation with interaction approach was applied to 
characterize TXA concentration and its effect on ML. Models were built hierarchically: a base 
model containing a structural component and a variability component was determined first, 
followed by the exploration of covariate models to explain the variability in the parameters. The 
graphic presentation of the data and output was performed using R (version 4.0.2)14 and ggplot2 
(version 3.0.0).15 
Pharmacokinetic modeling  
Base model development: One-compartment and two-compartment models with first-order 
elimination from the central compartment were explored and compared. One-compartment 
models were parameterized by clearance (CL) and central volume of distribution (Vc). 
Additional parameters including inter-compartmental clearance (Q) and peripheral volume of 
distribution (Vt) were used to parametrize the two-compartment models. Between subject 
variability (BSV) in all the PK parameters was assumed to be log-normally distributed as shown 
in Equation 1, where Pi denotes the individual parameter, tvP denotes the population typical 
parameter and Ƞi denotes the patient-specific deviation from the population parameters that 
follows a normal distribution with 0 as mean, ɷ2 as variance. 
𝑃𝑖= 𝑡𝑣𝑃 · 𝑒Ƞ𝑖
Equation 1 
Ƞ𝑖= (0, ɷ2) 


Different residual error models were also tested to account for the unexplained residual 
variability between observations and model predictions, including additive, proportional and 
combined (both additive and proportional) models. Equation 2 shows the formula of the 
combined error model. 𝑂𝐵𝑆𝑖,𝑗 and 𝐼𝑃𝑅𝐸𝐷𝑖,𝑗 are the observation and prediction for the ith patient 
at time j. The difference between these two variables was characterized by a proportional error 
term ɛ1𝑖,𝑗 and an additive error term ɛ2𝑖,𝑗 that follow normal distributions with mean at 0 and 
variance at 𝜎1𝑜𝑟2
2. 
𝑂𝐵𝑆𝑖,𝑗= 𝐼𝑃𝑅𝐸𝐷𝑖,𝑗 · (1 + ɛ1𝑖,𝑗) + ɛ2𝑖,𝑗
 Equation 2 
ɛ1𝑜𝑟 2𝑖,𝑗 ~ (0, 𝜎1𝑜𝑟2
2) 
Covariate model development: Covariate models were tested to leverage patient-specific 
covariates to explain the variability in parameters. Potential relationships were assessed from the 
graphical diagnosis first. Body weight was included in the model using allometric scaling to 
reflect the impact of organ size on PK. Given the hydrophilic properties of TXA, lean body mass 
(LBM) calculated by Boer equation16 was used in the allometry function to compare with total 
body weight. To explain clearance variability resulting from different levels of kidney functions, 
kidney function related covariates (Scr, CrCl) were tested upon clearance using a power 
function. 
The final model was chosen based on statistical diagnosis and graphical diagnosis. A model was 
determined to be significantly better if it reduced the objective function value (OFV) by more 
than 3.84 units (P < 0.05, for 1 degree of freedom). Covariates included in the final model are 
physiological or mechanistically relevant, and can explain the parameter variability significantly 
compared to the base model. 
Pharmacodynamic modeling 
A sequential population approach was used to perform the TXA concentration-ML analysis. This 
standard approach has been used previously.17 Briefly, first the PK was developed, and the 
individual predicted concentrations from the final PK model were used as an independent 
variable for the PD modeling. Due to the ex vivo characteristics of the ML bioassay, only direct 
effect models are reasonable. As shown in Equation 3, the PD model was parameterized in terms 


of baseline ML (ML0), maximal fractional inhibition (Imax), concentration of TXA causing 50% 
of maximal fractional inhibition (IC50), and hill factor (𝛾). Variabilities of all the parameters 
were assumed to be log-normally distributed. Different error models were evaluated and 
compared to account for the random residual variability. The effect of covariates on PD 
parameters was evaluated in the same manner as for PK parameters.       
Proportional PD effect model:    𝐸= 𝑀𝐿0 · (1 − 
𝐼𝑚𝑎𝑥 ·(𝑐𝑜𝑛𝑐_𝑝𝑟𝑒𝑑)𝛾
𝐼𝐶50𝛾+𝑐𝑜𝑛𝑐_𝑝𝑟𝑒𝑑𝛾)
Equation 3 
Model Evaluation 
Five-hundred bootstrap samples, each containing 30 patients, were generated by randomly 
sampling with replacement from the original dataset. Final PK and PD models from previous 
steps were used to re-estimate the parameters for the 500 bootstrap samples. Subsequently, the 
95% confidence interval of the bootstrap results was calculated.  
Simulations to derive optimal dosing 
In vitro studies have found that 10 mg/L of TXA is required to obtain 80% inhibition of 
fibrinolysis; thus, 10 mg/L was chosen as the PK therapeutic target.18,19 Based on data obtained 
from women after non-hemorrhagic deliveries, the normal reference of maximum lysis 17% was 
chosen as the PD therapeutic target.20 Individual TXA concentration and ML were simulated 
using a dose range of 100-1000 mg. The post-hoc individual parameters from the final PK and 
PD models were employed for the simulations.  The proportion of patients who met the PK or 
the PD targets were determined for each dosing regimen.