A Randomized Control Trial Assessing the Effect of Topical Tranexamic Acid on Risk of Hematoma in Breast Surgery
Phase: PHASE4
Conditions: Hematoma Postoperative
Sponsor: University of Michigan

A Randomized Control Trial Assessing the Effect of Topical 
Tranexamic Acid on Risk of Hematoma in Breast Surgery 
 
NCT05441592 
 
Date of IRB Approval: May 12, 2022 

PROTOCOL HUM NUMBER: HUM00210979 
 
PROTOCOL TITLE 
A Randomized Control Trial Assessing the Effect of Topical Tranexamic Acid on Risk of 
Hematoma in Breast Surgery 
 
 
Principal Investigator: 
Edwin Wilkins, MD 
 
 
 
 
Division of Plastic Surgery, Department of Surgery 
 
 
 
 
University of Michigan 
 
 
 
 
ewilkins@med.umich.edu 
 
Co-Investigator(s):  
Sherry Tang, MD 
 
 
 
 
Division of Plastic Surgery, Department of Surgery 
 
 
 
 
University of Michigan 
 
 
 
 
syqtang@med.umich.edu 
 
 
 
 
 
Jennifer Hamill, M.P.H 
 
 
 
 
Division of Plastic Surgery, Department of Surgery 
 
 
 
 
University of Michigan 
 
 
 
 
jenberry@med.umich.edu 
 
 
 
 
 
Lauren Bruce 
 
 
 
 
Division of Plastic Surgery, Department of Surgery 
 
 
 
 
University of Michigan 
 
 
 
 
labruce@med.umich.edu 
 
 
 
 
 
Investigational Agent(s)/How supplied: 
Drug name: Tranexamic Acid 
Pharmaceutical company name: Apollo Pharmaceuticals USA Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

HUM00210979 
 
Page 1 of 17 
ABBREVIATIONS 
 
AE 
 
Adverse Event 
CTSU  
Clinical Traisl Support Unit 
IRB 
 
Institutional Review Board 
IV 
 
Intravenously 
PI 
 
Pincipal Investigator 
SAE 
 
Serious Adverse Event 
TXA  
Tranexamic Acid 
UaP 
 
Unanticipated Problem 
 
 

HUM00210979 
 
Page 2 of 17 
STUDY SYNOPSIS 
Title 
A Randomized Control Trial Assessing the Effect of Topical 
Tranexamic Acid on Risk of Hematoma in Breast Surgery 
Phase 
Phase IV; Feasibility study 
Study Design 
Single blind 
Randomized 
Study Duration 
Enrollment duration: 24 months 
Subject follow-up duration: 4 weeks 
Overall study duration: 30 months 
Study Center(s) 
Single-center 
Objectives 
Evaluate the safety and efficacy of topical tranexamic acid use in 
preventing hematomas in routine breast plastic surgery operations 
Number of Subjects 500 
Disease/condition  
Incidence of hematoma occurance following breast surgeries 
Inclusion/Exclusion 
Criteria 
Inclusion Criteria 
• Patients aged 18 or over who are undergoing bilateral breast 
reduction or bilateral gender-affirming mastectomy 
• For patients undergoing bilateral breast reduction, any skin 
incision pattern or pedicle is acceptable 
• For patients undergoing bilateral gender-affirming mastectomy, 
any skin incision and mastectomy type is acceptable 
Exclusion Criteria 
• Active thromboembolic disease or history of intrinsic risk of 
thrombosis or thromboembolism, including retinal vein or artery 
occlusion 
• Current use of systemic anticoagulation 
• Hypersensitivity to tranexamic acid 
• Concomitant use of combined hormonal contraceptives 
• Use of factor IX complex concentrates, anti-inhibitor coagulant 
concentrates or all-trans retinoic acid 
• History of acquired defective color vision 
• History of subarachnoid hemorrhage 
• Pregnancy 
• History of renal impairment or serum Cr>1.5mg/dL 
Description of 
Study Intervention 
Patients undergoing breast reduction surgery or gender affirming 
mastectomy will be randomized to received intraoperative topical TXA 
irrigation vs no topical TXA irrigation. The patient will be followed for 
4 weeks postoperatively and the incidence of hematoma will be studied. 
Duration of 
Intervention 
Once intraoperatively 
Statistical 
Methodology 
Descriptive statistics of demographics and clinical characteristics of 
patients will be collected. The primary and secondary outcome will be 
presented as frequency counts and percentages and analyzed using 
Fisher’s exact test. 

HUM00210979 
 
Page 3 of 17 
STUDY SCHEMA 
 
 
Prior to 
Enrollment 
Total N = 500; Screen potential participants by inclusion and exclusion 
criteria. Obtain informed consent. 
Administer study intervention 
Evaluate primary and seconday outcomes 
Adverse events monitoring 
Randomize 
TXA 
N = 250 
Non-TXA 
N = 250 
Intraoperative 
Postoperative 

HUM00210979 
 
Page 4 of 17 
1.0 
BACKGROUND AND RATIONALE 
 
Reduction mammoplasty and gender-affirming mastectomy are two common plastic surgery 
operations that are generally performed in relatively healthy patients in the outpatient setting. 
Although these procedures are relatively safe and have a low complication profile, reoperations 
can occur due to hematomas1-2. The reported incidences of hematoma following reduction 
mammoplasty and gender-affirming mastectomy are around 3%-9% and 5%-10%, respectively3-
4. Most clinically significant hematoma will require operative washout or aspiration. If left 
untreated, hematomas can lead to nipple necrosis and skin flap compromise which can negatively 
impact patient satisfaction and aesthetic outcome.  
 
Tranexamic acid (TXA) has emerged over the past decade as an adjunctive pharmacologic agent 
to reduce intraoperative blood loss and prevent post-operative bleeding. Its mechanism involves 
inhibition of the conversion of plasminogen to plasmin which then prevents the breakdown of 
fibrin clots. The efficacy of tranexamic acid has been demonstrated in cardiac surgery, 
orthopedic surgery, spine surgery5-10. However, the use of tranexamic acid has not been routinely 
adapted into plastic surgery practice.  There have been some studies assessing the use of 
tranexamic acid in plastic surgery procedures, including facial aesthetic surgery, craniofacial 
surgery, and breast reconstruction11-17. In addition, the route of administration can include 
intravenous, oral, or topical. Some believe that the topical use of tranexamic acid provides a 
direct hemostatic benefit during surgery while decreasing systemic absorption14. The 
concentration of topical tranexamic acid has been reported from 1.5% to 3% in orthopedic 
surgery and aesthetic surgery14. Currently, the data suggests that tranexamic acid decreases 
intraoperative blood loss, postoperative bruising, and surgical drain output11-14. However, there is 
a paucity of randomized prospective data on the efficacy of topical tranexamic acid in reducing 
clinically significant reoperative hematomas in breast surgeries. 
 
This is a randomized control trial evaluating the efficacy of intraoperative topical tranexamic 
acid use in reduction mammoplasty and gender-affirming mastectomy. The primary outcome 
measure is the incidence of hematomas requiring operative intervention or aspiration. 
Secondarily, the occurrence of major thromboembolic events and other major complications will 
be assessed. This study hopes to further elucidate the safety and efficacy of topical tranexamic 
acid use in routine breast plastic surgery operations. 
 
2.0 
STUDY DESIGN, OBJECTIVES AND OUTCOME MEASURES 
2.1 
Primary Objectives 
 
To evaluate the safety and efficacy of topical tranexamic acid use in preventing 
hematomas in routine breast plastic surgery operations 
 
Primary Outcome Measure: 
1. Incidence of hematoma requiring operative intervention 
2.2 
Secondary Objectives  

HUM00210979 
 
Page 5 of 17 
 
To assess the safety profile of topical tranexamic acid when used as an intraoperative 
surgical irrigation 
 
Seconary Outcome Measure:  
1. Number of subjects experienging major thromboembolic events related to the 
study drug 
2. Number of subjectrs experiencing major complicatiosn other than hematoma 
 
3.0 
SUBJECT ELIGIBILITY 
Subjects must meet all of the selection criteria to be enrolled to the study. Study treatment may 
not begin until a subject has been consented and meets the eligibility criteria. 
3.1 
Inclusion Criteria 
o Patients aged 18 or over who are undergoing bilateral breast reduction or 
bilateral gender-affirming mastectomy 
o For patients undergoing bilateral breast reduction, any skin incision pattern or 
pedicle is acceptable 
o For patients undergoing bilateral gender-affirming mastectomy, any skin 
incision and mastectomy type is acceptable 
o Subjects must be able to understand/read/speak English 
 
3.2 
Exclusion Criteria 
• Active thromboembolic disease or history of intrinsic risk of thrombosis or 
thromboembolism, including retinal vein or artery occlusion 
• Current use of systemic anticoagulation 
• Hypersensitivity to tranexamic acid 
• Concomitant use of combined hormonal contraceptives 
• Use of factor IX complex concentrates, anti-inhibitor coagulant concentrates 
or all-trans retinoic acid 
• History of acquired defective color vision 
• History of subarachnoid hemorrhage 
• Pregnancy 
• History of renal impairment or serum Cr>1.5mg/dL 
 
4.0 
SUBJECT SCREENING, ENROLMENT, AND RECRUITMENT 
4.1 
Patient Screening and Recruitment 
Once a patient has been scheduled for either breast reduction or gender-affirming 
mastectomy, a member of the study team will conduct screening based on eligibility 
criteria and contact the patient using an IRB approved recruitment script to discuss the 
study and participation. Initial contact will either be made remotely, using the phone 

HUM00210979 
 
Page 6 of 17 
number or email address listed in MiChart or a message via the patient portal, or if time 
allows, in-person following the consultation in a private area. If they agree to participate, 
they will be asked to sign an electronic consent form. Hard copies of the consent 
document will be available also. 
4.2 
Randomization 
Patients will be randomized in a 1:1 ratio to either the TXA arm or the non-TXA arm. 
Randomization will occur pre-operatively in REDCap, the study’s data management 
system. 
4.3 
Blinding 
This study will be single-blinded. Patients will be blinded to the treatment. The surgical 
team will not be blinded. 
 
5.0 
TREATMENT PLAN 
5.1 
Drug dministration plan 
The surgical procedure will be performed according to standard practice determined by 
each individual surgeon. Topical TXA will be administered intraoperatively as a surgical 
irrigation. For patients randomized to the TXA arm, the breast pockets will additionally 
be irrigated with 150 cc of 2.67% TXA (75 cc in each breast). The TXA solution will be 
allowed to be sit in the breast pocket for 15 minutes and then removed after 15 minutes. 
In the non-TXA arm, breast pockets will not receive additional irrigation. 
 
Table 1. Drug Administration Plan 
Agent 
Dose 
Route 
Schedule 
Tranexamic 
Acid 
Total dose: 150 cc of 2.67% TXA 
Dose per breast: 75 cc of 2.67% TXA 
Topical 
Administer once intraoperative 
as a surgical irrigation 
 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Each subject will be assessed for the development of toxicity according to the Time and 
Events Table (Section 6.3).  
5.3 
Concomitant Medications/Treatments 
Concomitant drugs and/or treatments that are prohibited including the following: 
• Concomitant use of systemic anticoagulation 
• Concomitant use of combined hormonal contraceptives 
• Concomitant use of factor IX complex concentrates, anti-inhibitor coagulant 
concentrates or all-trans retinoic acid 
5.4 
Duration of Therapy 
The study drug will be administered once intraoperatively with a total duration of 15 
minutes. 
 

HUM00210979 
 
Page 7 of 17 
Administration of treatment may continue unless one of the following criteria apply: 
• Inter-current illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Subject voluntarily withdraws from treatment OR 
• General or specific changes in the subject’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator 
5.5 
Off Treatment Criteria  
Subjects will be removed from protocol therapy when any of the criteria listed in Section 
5.4 apply. Subjects who discontinue treatment will continue protocol specific follow-up 
procedures as outlined in Section 5.6. The only exception to this requirement is when a 
subject withdraws consent for all study procedures or loses the ability to consent freely. 
5.6 
Duration of Follow-Up 
Patients will be followed for 4 weeks postoperatively. The follow-up timeline will be 
dictated by each surgeon’s standard practice, but will generally consist of 2 visits, one 
approximately 1 week after surgery and a second approximately 4 weeks after surgery.  
5.7 
Off Study Criteria 
Subjects can be taken off study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral, or administrative 
reasons. The reason(s) for discontinuation from study will be documented and may 
include: 
1. Subject withdraws consent (termination of treatment and follow-up); 
2. Loss of ability to freely provide consent through imprisonment; 
3. Subject is unable to comply with protocol requirements; 
4. Treating physician judges that continuation on the study would not be in the 
subject’s best interest; 
5. Subject becomes pregnant; 
6. Lost to Follow-up. If a research subject cannot be located for 1 year, the subject 
may be considered “lost to follow-up.” All attempts to contact the subject during 
the one year must be documented; 
7. Termination of the study by the investigators or the University of Michigan 
8. Subject completes protocol treatment and follow-up criteria. 
5.8 
Subject Replacement 
The subjects will not be replaced. 
 
6.0 
STUDY PROCEDURES AND EFFICACY ASSESSMENT 
6.1 
Study Procedures and Efficacy Assessments 
 
Surgical technique 
 

HUM00210979 
 
Page 8 of 17 
Patients will undergo their breast reduction surgery or gender-affirming mastectomy 
based on standard surgical technique by each surgeon. For patients undergoing breast 
reduction, there are no requirements on the method of skin incisions or type of pedicle 
used. This decision will be per individual surgeon judgement. For patients undergoing 
gender-affirming mastectomy, there are also no requirements on the method of skin 
incision and type of mastectomy. This will be per individual surgeon judgement. Once 
the surgeon has completed resecting the breast tissue, the weight of the resected tissue 
will be recorded. Hemostasis will be achieved in the standard fashion using 
electrocautery and the surgical sites may be irrigated according to each surgeon's 
preference. Next, for patient randomized to the TXA arms, the breast pockets will 
additionally be irrigated with 150 cc of 2.67% TXA (75 cc in each breast). The TXA 
solution will be allowed to be sit in the breast pocket for 15 minutes and then removed 
after 15 minutes. In the non-TXA arm, each breast pocket will not receive additional 
irrigation. The surgical sites will then be closed in a fashion that is determined by the 
individual surgeon. The use of postoperative drains and surgical compression garment 
will also be per the individual surgeon. 
 
Follow-up 
 
Patients will be followed for 4 weeks postoperatively. The follow-up timeline will be 
dictated by each surgeon’s standard practice, but will generally consist of 2 visits, one 
approximately 1 week after surgery and a second approximately 4 weeks after surgery. 
The primary and secondary outcomes of the study will be collected by a study team 
member via chart review. 
 
Any adverse events will also be collected up to 30 days after surgery. Adverse events 
include the following: 
• Hematoma 
• Seroma 
• Re-operation 
• Infection 
• Wound dehiscence 
• Skin necrosis 
• Rash 
• Thromboembolic events (DVT, PE) 
• Hypersensitivity reaction 
• Seizures 
• Vision change 
6.2 
Safety/Tolerability 
Analyses will be performed for all subjects having received the study drug (See Section 
8.0). 
 
 
 
 

HUM00210979 
 
Page 9 of 17 
 
6.3 
Time and Events Table 
Study Element 
Pre-Op 
Day of 
Surgery 
Post-op (until 4 
weeks after surgery) 
Informed Consent 
X 
 
 
Demographics 
X 
 
 
Eligibility 
X 
 
 
BMI 
X 
 
 
Comorbidities 
X 
 
 
Smoking status 
X 
 
 
Study intervention 
 
X 
 
Resection weight(s) 
 
X 
 
Surgical technique (including 
incision type and pedicle type) 
 
X 
 
Use of surgical drains 
 
X 
 
Estimated blood loss 
 
X 
 
Need for transfusion 
 
X 
 
Use of postoperative 
compression wrap or garments 
 
X 
X 
Surgical complications 
 
X 
X 
Adverse events 
 
X 
X 
 
7.0 
ADVERSE EVENTS 
7.1 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and 
is done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Data on adverse events will be collected 
from the time of the initial study treatment or intervention through 30 days after the last 
dose of study treatment or intervention. Any serious adverse event that occurs more than 
30 days after the last study treatment or intervention and is considered related to the study 
treatment or intervention must also be reported. Serious Adverse Events (SAEs) will 
continue to be followed until: 
• Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
• There is satisfactory explanation other than the study treatment or intervention for 
the changes observed; or  
• Death. 
 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The 
definitions of AEs and SAEs are given below. It is the responsibility of the principal 

HUM00210979 
 
Page 10 of 17 
investigator to ensure that all staff involved in the trial is familiar with the content of this 
section. 
 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration or intervention is considered to be pre-existing in nature. Any 
known pre-existing conditions that are ongoing at time of study entry should be 
considered medical history. 
 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.3, 
occurring from the initial study treatment administration or intervention through 30 days 
following the last dose of the study treatment or study intervention must be recorded as 
an adverse event in the subject’s source documents and on the CRF regardless of 
frequency, severity (grade) or assessed relationship to the study treatment or intervention.  
 
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) 
of a pre-existing condition that occurs after the subject begins study treatment or 
intervention is also considered an adverse event. 
 
Review of AE and SAE data will be performed on a routine basis by the study team. 
7.2 
Definitions 
7.2.1 Adverse Event 
 
Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a subject 
participating in an investigational study or protocol regardless of causality 
assessment.  An adverse event can be an unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, syndrome or 
disease associated with or occurring during the use of an investigational 
product whether or not considered related to the investigational product. 
 
Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) 
procedures will not be reported as adverse events. However, the medical 
condition for which the procedure was performed must be reported if it 
meets the definition of an adverse event unless it is a pre-existing (prior to 
protocol treatment) condition. 
 
7.2.2 Serious Adverse Event 
An adverse event is considered “serious” if, in the view of the investigator, 
it results in any of the following outcomes: 
 
• Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 

HUM00210979 
 
Page 11 of 17 
• A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of 
either the investigator,its occurrence places the subject at immediate 
risk of death. It does not include an adverse event that, had it occurred 
in a more severe form, might have caused death.  
 
• Inpatient hospitalization or prolongation of existing hospitalization for 
> 24 hours. 
 
• A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions 
 
• A congenital anomaly/birth defect 
 
• Important medical event 
Any event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon 
appropriate medical judgment, it may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes 
listed in this definition of  “Serious Adverse Event.” Examples of such 
medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; convulsions that do not 
result in inpatient hospitalization or the development of drug 
dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries 
should not be reported as SAEs unless the underlying medical condition 
has worsened during the course of the study. Preplanned hospitalizations 
or procedures for preexisting conditions that are already recorded in the 
subject’s medical history at the time of study enrollment should not be 
considered SAEs. Hospitalization or prolongation of hospitalization 
without a precipitating clinical AE (for example, for the administration of 
study therapy or other protocol-required procedure) should not be 
considered SAEs. However, if the preexisting condition worsened during 
the course of the study, it should be reported as an SAE. 
 
7.2.3 Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
• For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Insert (Label).  
• For investigational new drugs or devices, those adverse events are 
described in the FDA Investigator’s Brochure.  
• In clinical research studies, information on expected adverse events is 
also summarized in the protocol and in the consent document.  See 
section 8.1 for the list of expected adverse events related to the drug 
under study. 

HUM00210979 
 
Page 12 of 17 
 
7.2.4 Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in 
the Package Insert, Investigator’s Brochure, in published medical 
literature, in the protocol, or in the informed consent document.  
7.3 
Adverse Event Characteristics 
7.3.1 Terms and Grading 
 
The severity or grade of an adverse event may be measured using the 
following definitions: 
 
Mild:  Noticeable to the subject, but does not interfere with subject’s 
expected daily activities, usually does not require additional therapy or 
intervention, dose reduction, or discontinuation of the study. 
 
Moderate:  Interferes with the subject’s expected daily activities, may 
require some additional therapy or intervention but does not require 
discontinuation of the study. 
 
Severe: Extremely limits the subject’s daily activities and may require 
discontinuation of study therapy, and/or additional treatment or 
intervention to resolve. 
 
7.3.2 Attribution of the AE 
The investigator or co-investigator is responsible for assignment of 
attribution. 
Definite – The AE is clearly related to the study treatment/intervention. 
Probable – The AE is likely related to the study treatment/intervention. 
Possible – The AE may be related to the study treatment/intervention. 
Unlikely – The AE is doubtfully related to the study 
treatment/intervention. 
Unrelated – The AE is clearly NOT related to the study 
treatment/intervention. 
7.4 
Serious Adverse Event Reporting Guidelines 
7.4.1 The Principal Investigator must be notified within 7 business day of study 
team’s knowledge of any event meeting the criteria and definition of a 
serious adverse event, regardless of attribution, occurring during the study 
or within 30 days of the last administration of the study related 
treatment/intervention. 
7.4.2 The investigator must report all events meeting the criteria and definition 
of a serious adverse event as per the local IRB reporting requirements.  
7.5 
Reporting of Unanticipated Problems 

HUM00210979 
 
Page 13 of 17 
Unanticipated problem: Per FDA Procedural Guidance for Clinical Investigators, 
Sponsors, and IRBs (January 2009), an unanticipated problem is defined as a 
serious problem that has implications for the conduct of the study (requiring a 
significant and usually safety-related, change in the protocol (such as revising 
inclusion/exclusion criteria or including a new monitoring requirement), informed 
consent or investigator’s brochure). 
 
Upon becoming aware of any incident, experience, or outcome (not related to an 
adverse event) that may represent an unanticipated problem, the investigator 
should assess whether the incident, experience, or outcome represents an 
unanticipated problem. The incident, experience, or outcomes is considered 
unanticipated if it meets all of the following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of harm 
than was previously known or recognized. 
 
Unanticipated problem Reporting: Per 21 CFR 312.66, 312.53 (c)(1)(vii), and 
56.108(b)(1), should an Unanticipated problem occur during the investigation, the 
investigator will promptly report all unanticipated problems involving risks to 
human subjects or others to the IRB. 
 
8.0 
DRUG INFORMATION 
8.1 Tranexamic Acid (TXA) 
 
See following link to drug insert for more details: 
https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a30cd382-4e2a-428d-
a6d1-a530f4d230c1&type=display 
 
• Manufacturer: Apollo Pharmaceuticals USA Inc. 
 
• Route of administration: The drug use for this study is approved for IV use. The drug 
will be used topically for this study. 
 
• Mode of action: TXA inhibits of the conversion of plasminogen to plasmin which 
then prevents the breakdown of fibrin clots. 
 
• Pharmacokinetics:  
 
• Distribution: The initial volume of distribution is about 9-12 liters. The 
plasma protein binding of tranexamic acid is about 3% at therapeutic 
plasma levels and seems to be fully accounted for by its binding to 
plasminogen. Tranexamic acid does not bin to serum albumin. 

HUM00210979 
 
Page 14 of 17 
 
• Elimination: After an IV dose of 1 g of TXA, the plasma concentration 
time curve shows a triexponential decay with half-life of about 2 hours for 
the terminal elimination phase. 
 
• Excretion: Urinary excretion is the main route elimination via glomerular 
filtration. Overall renal clearance is equal to overall plasma clearance 
(110-116 mL/min), and more than 95% of the dose is excreted in the urine 
as unchanged drug. Excretion of tranexamic acid is about 90% at 24 hours 
after IV administration of 10 mg/kg body weight. 
 
• Contraindications: Subarachnoid hemorrhage, active intravascular clotting 
 
• Potential Side Effects: Thromboembolic events, seizures, hypersensitivity reactions, 
visual disturbances, dizziness 
 
• Drug Interactions: No studies of interactions beteen tranexamic acid and other drugs 
have been conducted. 
 
• Storage and Stability: Store at 20 C to 25 C 
 
• Preparation Dispensing, and Labeling:  
The TXA solution will be prepared by the University of Michigan OR pharmacy.  
The drug will be prepared according to the following table.  
 
 
Concentration 
Volume 
Tranexamic acid 
100 mg/ml  
40 ml 
Sodium chloride 
0.9% 
110 ml 
Final 
4000 mg/150 ml 
150 ml 
 
The prepared solution is to be used within 6 hours on the same day of the preparation.  
 
• Availability: Commercially available  
 
• Return and Retention of Study Drug: The remaining/expired/used or returned drug is 
to be destroyed on site. The drug destruction is according to the institution standard 
operating procedure for drug destruction 
 
• Drug Accountability: The University of Michigan OR Pharmacy will be providing the 
drug and managing the drug supply according to the institution stanard operating 
procedures. 
 
9.0 
STATISTICAL CONSIDERATIONS 
 

HUM00210979 
 
Page 15 of 17 
Sample size calculation was performed for a 50% reduction in hematoma requiring operative 
intervention or aspiration.  The study would have 80 percent power to detect the expected 50 
percent risk reduction (assuming α = 0.05, β = 0.20, n1:n2 of 1:1) if 250 patients are enrolled in 
each cohort. 
 
Descriptive statistics of demographics and clinical characteristic of patients will be calculated. 
The descriptive statistics will be compared between the two treatment arms to assess any obvious 
imbalance in risk factors, despite the use of randomization. 
 
A primary goal of the study is to evaluate the rate of hematoma requiring operation washout or 
aspiration in patients who receive topical TXA versus patients who do not receive topical TXA  
intraoperatively during breast reduction or gender-affirming mastectomy. This data will be 
presented as frequency counts and percentages and analyzed using Fisher’s exact test. A value of 
p < 0.05 is considered statistically significant. 
 
10.0 DATA AND SAFETY MONITORING 
 
The study team is required to meet at least quarterly to discuss matters related to: 
• Enrollment rate relative to expectations, characteristics of participants 
• Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
• Adherence to protocol (protocol deviations) 
• Completeness, validity and integrity of study data 
• Retention of study participants 
 
11.0 REGULATORY 
11.1 
Institutional Review Board (IRB) 
Before implementing this study, the protocol, the proposed informed consent form and 
other information to be provided to subjects, must be reviewed and approved by a 
properly constituted IRB. Any amendments to the protocol must be reviewed and 
approved by the IRB. 
11.2 
Subject Information and Consent 
Study team member will explain to each subject (or legally authorized representative) the 
nature of the study, its purpose, the procedures involved, the expected duration, the 
potential risks and benefits involved and any discomfort it may entail.  Each subject will 
be informed that participation in the study is voluntary and that he/she may withdraw 
from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
 
This informed consent will be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before 
signing and dating it, and should be given a copy of the signed document. If the subject 
cannot read or sign the documents, oral presentation may be made or signature given by 
the subject’s legally appointed representative, if witnessed by a person not involved in the 

HUM00210979 
 
Page 16 of 17 
study, mentioning that the subject could not read or sign the documents. No subject can 
enter the study before his/her informed consent has been obtained. 
 
The informed consent form is considered to be part of the protocol, and will be submitted 
for IRB approval. 
 
12.0 REFERENCES 
 
1. Wilson SC, Morrison SD, Anzai L, Massie JP, Ooudrier G, Motosko CC, Hazen A. 
Masculinizing top surgery: a systematic review of techniques and outcomes. Annals 
of Plas Surg 2018; 80(6): 679-83. 
2. Aravind P, Siotos C, Bernatowicz E, Cooney CM, Rosson GD. Breast reduction in 
adults: identifying risk factors for overall 30-day postoperative complications. 
Aesthetic Surg J 2020; 40(12): 676-85. 
3. Pannucci CJ, Wachtman CF, Dreszer G, Bailey SH, Portschy PR, Hamill JB, Hume 
KM, Hoxworth RE, Kalliainen LK, Rubin JP, Pusic AL, Wilkins EG. The effect of 
postoperative enoxaparin on risk for reoperative hematoma. Plast Reconstr Surg 
2012; 129(1): 160-68. 
4. Lang CL, Day DL, Klit A, Mejahl MK, Holmgaard R. Low risk of persistent pain, 
sensory disturbances, and and complications following mastectomy after gender-
affirming surgery. Transgend Health, 2021; 6(4): 188-923. 
5. Gausden EB, Qudsi R, Boone MD, O’Gara B, Ruzbarsky JJ, Lorich DG. Tranexamic 
acid in orthopaedic trauma surgery: a meta-analysis. J Orthop Trauma 2017; 31(10): 
513-19. 
6. Yerneni K, Burke JF, Tuchman A, Li X, Metz LN, Lehman RA, Lenke LG, Tan LA. 
Topical tranexamic acid in spinal surgery: a systematic review and meta-analysis. J 
Clin Neurosci 2019; 61:114-19. 
7. Fawzy H, Elmistekawy E, Bonneau D, Latter D, Errett L. Can local application of 
tranexamic acid reduce porst-coronary bypass surgery blood loss? A randomized 
control trial. J Cardiothoracic Surg, 2009; 4:25. 
8. Dell’Amore A, Caroli G, Nizar A, Cassanelli N, Luciano G, Greco D, Dolcio G, Bini 
A, Stella F. Can topical application of tranexamic acid reduce blood loss in thoracic 
surgery? A prospective randomized double blind investigation. Heart, Lung and 
Circulation, 2012; 21:706-610. 
9. Alshryda S, Sukeik M, Blenkinsopp Jj, Haddad FS, Mason JM. A systematic review 
and meta-analysis of the topical administration of tranexamic acid in total hip and 
knee replacement. Bone Joint J, 2014; 96-B: 1005-15. 
10. Ren Z, Li S, Sheng L, Zhuang Q, Li Z, Xu D, Chen X, Jiang, P, Zhang X. Topical use 
of tranexamic acid can effectively decrease hidden blood loss during posterior lumbar 
spinal fusion surgery. Medicine, 2017; 96:42(e8233). 
11. Weissler JM, Banuelos J, Jacobson ST, Manrique OJ, Nguyen MT, Harless CA, Tran 
NV, Martinez-Jorge J. Intravenous tranexamic acid in implant-based breast 
reconstruction safely reduces hematoma without thromboembolic events. Plast Rec 
Surg 2020; 146(2): 238-45. 

HUM00210979 
 
Page 17 of 17 
12. Locketz GD, Lozada KN, Bloom JD. Tranexamic acid in aesthetic facial plastic 
surgery: a systematic review of evidence, applications, and outcomes. Aesthetic 
Surgery J Open Forum, 2020; 1-9.  
13. Scarafoni EE. A systematic review of tranexamic acid in plastic surgery: What’s 
new? Plast Reconstr Surg Glob Open, 2021; 9:e3172. 
14. Rohrich RJ, Cho MJ. The role of tranexamic acid in plastic surgery: Review and 
technical considerations. Plast Reconstr Surg, 2018; 141: 507-515. 
15. Laikhter E, Comer CD, Shiah E, Manstein SM, Bain PA, Lin SJ. A systematic review 
and meta-analysis evaluating the impact of tranexamic acid administration in 
aesthetic plastic surgery. Aesthet Surg J 2021; Online ahead of print. 
16. Ausen K, Hagen AI, Ostbyhaug HS, Olafsson S, Kvalsund BJ, Spigset O, Pleym H. 
Topical moistening of mastectomy wounds with diluted tranexamic acid to reduce 
bleeding: randomized clinical trial. Brit J Surg Open 2020; 4: 216-24. 
17. Murphy GRF, Glass GE, Jain A. The efficacy and safety of tranexamic acid in cranio-
maxillofacial and plastic surgery. J Craniofac Surg 2016; 27(2): 374-79.