The Impact of Tranexamic Acid in Reducing Hematoma and Seroma Formation in Reconstructive Post-oncologic Breast Surgery
Phase: PHASE4
Conditions: Breast Cancer
Sponsor: University of California, San Francisco

The Impact of Topical Tranexamic Acid in Breast Reconstruction 
Protocol Number:  CC # 228012 
Investigational Product(s):  Topical Tranexamic Acid 
Version Number:  v4 
Version Date:  1/26/24 
IND Number:  N/A 
NCT Number: 05807074 
Principal Investigator (Sponsor-Investigator) 
Merisa Piper, MD 
University of California, San Francisco 
Statistician 
Chiung-Yu Huang, PhD 
UCSF Surgery Biostatistics Core 
Revision History 
Version 2 
08/12/2022 
Version 3 
09/27/2022 

Protocol Signature Page 
 
 
1. I agree to follow this protocol version as approved by the UCSF Protocol Review and 
Monitoring Committee (PRMC), Institutional Review Board (IRB), and Data and 
Safety Monitoring Committee (DSMC).  
2. I will conduct the study in accordance with the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Good Clinical Practices (GCP) and the applicable IRB, ethical, federal, state, and 
local regulatory requirements.  
3. I certify that I, and the study staff, have received the required training to conduct this 
research protocol.  
4. I agree to maintain adequate and accurate records in accordance with IRB policies, 
federal, state and local laws and regulations. 
 
UCSF Principal Investigator  
 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
 

        

Abstract 
Title 
The impact of topical Tranexamic Acid in reconstructive post-
oncologic breast surgery 
Study Description Improvement in bleeding and bruising has been described by 
using both intravenous and topical off-label applications of 
Tranexamic Acid (TXA) in many surgical fields. The proposed 
prospective study will evaluate the utility of topical tranexamic 
acid in decreasing hematoma and seroma rates, drain output, 
and ecchymosis in post-mastectomy breast reconstruction 
patients. This novel use of TXA in breast surgery may provide a 
simple, cost-effective, and safe way to improve outcomes and 
satisfaction for our breast cancer patients. 
Phase of Study 
Phase 2 
Investigational 
Products 
 
Tranexamic Acid (Topical application) 
 
Study population 
Female patients > 18 years old undergoing bilateral mastectomy 
with reconstruction or complex closure 
Primary Objective To investigate whether topical tranexamic acid may impact rates 
of seroma, hematoma, severe bruising, and drain output in the 
post-mastectomy reconstructive population 
 
Sample Size 
The goal enrollment is 150 patients undergoing bilateral 
mastectomy, or 300 breasts. Given that the literature cites a 
hematoma rate of up to 5% in post mastectomy patients, if we 
aim for complete reduction with TXA, we will need at least 150 
per group to be adequately powered to detect that difference 
(alpha 0.05, beta 0.2). However, since complete reduction is not 
realistic, we will aim to recruit as many as possible with a 
minimum goal of 150 patients, which will give us 300 breasts 
total such that 150 breasts will receive TXA and 150 breasts 
saline.  
 
Duration of Study 
Treatment 
Participants will only be treated intraoperatively at the time of 
surgery with topical TXA to one breast pocket.  

Duration of 
Follow up 
We routinely follow post-mastectomy patients up to 1 year after 
their surgery. The standard post-operative follow-up regimen 
includes appointments at 1 week, 2 weeks, 6 weeks, 3 months, 
and 1 year, followed by yearly appointments thereafter. 
However, the schedule and number of visits will vary by patient. 
Patients in this study will be assessed at their regularly 
scheduled visits up to one year post-operatively. 
 
Unique Aspects 
of this Study 
This study is the first in the United States to evaluate the impact 
of topical Tranexamic Acid on hematoma, seroma, drain output, 
drain duration, and subjective bruising following post-
mastectomy breast reconstruction, utilizing each patient as their 
own internal control.  
 
 
 

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1 Introduction 
1.1 Background on Indication 
Post-mastectomy breast reconstruction has significant physical, mental and 
emotional benefits for breast cancer patients[1]. However hematoma, seroma and 
bruising are common complications given the highly vascularized nature of breast 
tissue[2]. These events can compromise the reconstruction, as well as potentially delay 
cancer treatments including chemotherapy and radiation by predisposing the patient to 
infection and wound complications. The hematoma and subsequent reoperation rate in 
breast surgery has been cited from 2-5% [2], thus topical hemostatic agents are often 
used intraoperatively. However, these agents are usually expensive, come in varying 
forms, and difficult to regulate. Prior studies in orthopedics, plastic surgery, and trauma 
have shown a significant reduction in bleeding, ecchymosis, and need for transfusions 
with use of Tranexamic Acid (TXA)[3-12]. TXA is a synthetic amino acid that blocks 
plasminogen conversion to plasmin, to prevent fibrinolysis and stabilize clot formation. 
Improvement in bleeding and bruising has been described utilizing both intravenous and 
topical off-label applications of TXA[6, 12]. In breast surgery there have been mixed 
results to preliminary retrospective studies of both intravenous and topical tranexamic 
acid, with some decreases in hematoma and seroma rates, and drain volumes[13-15]. 
The proposed prospective trial will evaluate the efficacy of topical TXA in decreasing 
hematoma and seroma rates, drain output, drain duration, and ecchymosis in bilateral 
post-mastectomy breast reconstruction patients. Every patient will serve as their own 
control. This novel use of TXA in breast surgery may provide a simple, cost-effective, 
and safe way to improve outcomes in breast reconstruction patients.  
1.2 Background on the Investigational Product(s) and Associated Known 
Toxicities 
TXA is a synthetic amino acid that blocks plasminogen conversion to plasmin to 
stabilize clot formation [16]. Despite the fact that TXA is only FDA-approved for 
hemophilia patients to reduce hemorrhage and need for replacement therapy following 
tooth extraction [16], many high powered double-blind randomized trials have published 
their results using TXA in other surgical specialties. Prior orthopedic arthroplasty studies 
have shown that a single intraoperative dose of TXA prior to incision significantly 
decreases blood loss and transfusion requirements without associated thrombotic 
complications [6, 7, 11, 17]. These have shown that not only intravenous, but also 
directly infiltrating the joint topically can decrease bleeding [6, 12]. Furthermore, there 
have not been any report of increased systemic thrombosis when used topically. In 
plastic surgery, TXA is routinely dosed intravenously prior to incision for pediatric 
craniosynostosis cases to minimize blood loss, decrease transfusion requirements, and 
shorten length of hospital stay [3, 4, 9]. The literature also shows when used topically it 
can significantly decrease bruising and bleeding in rhinoplasty, rhytidectomy, and 
liposuction [8, 10, 18, 19]. 
 
More recently, there have been retrospective studies in breast plastic and oncologic 
surgery evaluating the use of TXA without any evidence of thrombotic complications. 
Weissler et al published a retrospective review of immediate post-mastectomy tissue 

expander placement which showed a statistically significant decrease in hematoma with 
intravenous TXA administration[13].  Perhaps most pertinent for our study is the small 
trial from Ausen et al in the Netherlands in which they examined topical moistening of 
mastectomy flaps with a dilute TXA solution. They found no complications were related 
to topical administration of TXA relative to the control group[15]. This small study 
trended toward decreasing hematoma rates and drain volumes, and inspired our own 
study design of using each patient as their own internal control. We hope to build off this 
study given our large volume of mastectomies, and low risk profile of utilizing topical 
TXA. Additionally, designing the study such that each patient receives a control and 
experimental dose (saline on one side, TXA on the other) will help us to control for any 
confounding patient factors and further validate our results.  
 
Given the mechanism of action of TXA, there is the theoretical complication of 
perpetuating thrombotic events due to inhibition of clot breakdown[16]. There have been 
no documented events of venous thromboembolism in relation to topical administration 
of TXA in plastic surgery procedures, which are the most relevant to our proposed 
study[6, 8, 14, 15, 18]. One prior study in trauma patients showed an increased risk of 
pulmonary embolism/or deep venous thrombosis with TXA[20]. However, this was a 
study regarding repetitive intravenous dosing, and in a uniquely sick patient population 
in extremis, with disseminated intravascular coagulation due to acute traumatic blood 
loss and therefore not directly applicable to our proposed study.  Other side effects 
associated with intravenous tranexamic acid include hypersensitivity reactions, 
seizures, visual disturbances, and dizziness[16]. The latter three would not apply to our 
study given that with topical tranexamic acid, the drug will not cross the blood brain 
barrier and thus would not elicit neurologic adverse effects.  
 
1.3 Rationale for the Proposed Study 
The proposed prospective trial will evaluate the utility of topical tranexamic acid in 
decreasing hematoma, seroma, and ecchymosis in post-mastectomy breast 
reconstruction patients. We currently use several topical intraoperative hemostatic 
agents including Arista, Surgicell, and Teseal. These have varying efficacy, inconsistent 
data, and greater cost than TXA which is produced in many generic formulations. Given 
that prior literature demonstrates TXA is effective in improving hematoma and bleeding 
outcomes with no proven risk, especially when applied topically, our goal is to 
investigate the potential of topical TXA to decrease rates of post-operative bleeding, 
hematoma, seroma, drain volume, and bruising. This work is significant because TXA 
offers a cheaper, time-efficient, and simple way to potentially improve outcomes post-
mastectomy. Each patient will serve as their own internal control by design, there is no 
greater risk to any one patient in the study over others. Additionally, if we find that TXA 
helps with post-operative outcomes and offers a cheaper alternative to various other 
hemostatic agents on the market, this benefits the hospital and patient.  
1.4 Rationale for the TXA Dose Selection/Regimen  
Each patient will have one breast exposed to TXA and the other to saline. Prior 
literature has safely demonstrated the topical application of 1 gram of TXA in patients 

undergoing joint replacement surgery[12]. TXA is readily available in the anesthesia cart 
of the operating room in a sterile, single-dose 1g/ml vial that needs to be reconstituted 
in 1ml of saline. This can then be added to 40ml of 0.9% normal saline to dilute it to 
25mg/ml TXA solution. 20cc of this can then be infiltrated into the breast pocket, which 
would only expose the patient to 500mg of TXA to that side. With prior evidence to 
suggest 1 gram of TXA is safe, we are well within the range of TXA that can be safely 
administered. Additionally, this 20cc of solution can easily fit into a breast pocket without 
leaking and/or affecting skin closure. 20cc of 25mg/ml solution was also previously 
described in the small trial by Ausen et al and serves as the model for this study 
design[15].   
There will only be one application of topical TXA and this will be administered 
intraoperatively, without subjecting patients in theory to systemic risks.  
 
2 Study Objectives  
2.1 Hypothesis 
Given the use of topical tranexamic acid in reducing bleeding and bruising in other 
surgical specialties, we believe that topical tranexamic acid can improve post-operative 
outcomes after breast cancer surgery in a cost-effective manner. We hypothesize that 
the use of topical TXA in the breast pocket prior to closure will lead to a significantly 
lower rate of breast hematoma or seroma requiring intervention, decrease overall drain 
output, and decrease subjective bruising when compared to the control breasts.  
2.2 Primary Objective and Endpoint(s) 
The primary objective of this study is to evaluate the impact of topical TXA versus 
control (saline) on key post-operative outcome measures. These include hematoma, 
seroma, drain output, drain duration, bruising, and reoperation. 
Primary Objective 
Endpoint(s) 
Time Frame 
1. To evaluate the impact of TXA on 
hematoma rates compared to control 
Presence of 
hematoma in 30 
day period 
From 
application in 
the operating 
room to 30 
days of follow 
up 
2. To evaluate the impact of TXA on 
seroma rates compared to control 
Presence of 
seroma in 3 month 
period 
From 
application in 
the operating 
room to 3 
months of 
follow up 
 

2.3 Secondary Objective(s) and Endpoint(s) 
Secondary Objective 
Endpoint(s) 
Time Frame 
1. To evaluate the impact of TXA on patient 
and provider rating of bruising, comparing 
the TXA side to the control side 
• Ecchymosis will 
be compared 
between the 
right and left 
side at each 
post operative 
visit and 
documented. 
The observer 
will be blinded 
to the laterality 
of TXA  
From 
application in 
the operating 
room to 30 
days of 
follow up 
2. To evaluate the impact of TXA on total 
drain output in the first post operative day 
• Total drain 
output over the 
life of the drain, 
compared 
between control 
and study 
groups 
From drain 
placement in 
the operating 
room to 
discharge on 
POD1  
3. To evaluate the impact of TXA on total 
drain duration 
• Total drain 
duration 
compared 
between control 
and study 
groups 
From drain 
placement in 
the operating 
room to 
removal of 
the drain  
 
3 Study Design 
3.1 Characteristics 
We propose a prospective, placebo-control trial looking at the effect of topical 
tranexamic acid on post-operative bleeding, hematoma, seroma, drain output, and 
bruising in post-mastectomy breast reconstruction. We will recruit patients undergoing 
bilateral mastectomy at our institution. Patients will be excluded if they have previous 
history of bleeding or coagulation disorders. Each patient will serve as their own internal 
control, with one side receiving saline and the other TXA. During surgery and prior to 
wound closure, we will moisten the wound surface of one side with 20 cc of dilute TXA 
25mg/ml solution, and the contralateral with 20cc of saline. Demographics, cancer 
details, and surgical characteristics will be collected. Outcomes will we assess include 
hematoma, seroma, reoperation, drain duration, and degree of ecchymosis will be 
recorded post-operatively for analysis over a 3-month period. The primary outcome will 

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During surgery, after removal of breast 
tissue and prior to closure 
One side Breast Skin Flap: soaked with 20ml of 25mg/ml TXA solution 
One side Breast Skin Flap; soaked with 20ml of 0.9% normal saline (control) 
 
3.7 Duration of Follow Up 
Patients are routinely followed for at least one year after undergoing post-mastectomy 
breast reconstruction and monitored for the development of any of the outcomes of 
interest and assessed for drain removal. Patients in this trial will be seen per our 
standard follow-up care, which typically involves a post-operative visit in the 1-4 week 
period, in the 5-11 week period, and some time in the 12 week to 1 year period. The 
exact number and schedule of visits vary by patient and their needs. Our study-specific 
assessment and procedures will occur at each of these regularly scheduled visits up to 
one year after surgery. Regarding AEs, Given the mechanism of action of TXA, there is 
the theoretical complication of perpetuating thrombotic events due to inhibition of clot 
breakdown[16]. There have been no documented events of venous thromboembolism in 
relation to topical administration of TXA in plastic surgery procedures, which are the 
most relevant to our proposed study[6, 8, 14, 15, 18]. Other side effects associated with 
intravenous tranexamic acid include hypersensitivity reactions, seizures, visual 
disturbances, and dizziness[16]. The latter three would likely not apply to our study 
given that with topical tranexamic acid, the drug will not cross the blood brain barrier 
and thus would not elicit neurologic adverse effects. 
 
However if any patient develops these signs of symptoms, the TXA will immediately be 
removed from their system via washout in the operating room. If they later develop 
signs or symptoms of post-operative bleeding, hematoma, or seroma to their breast, 
they will be cared for per the standard of care which may involve aspiration, drain 
placement, or return to the operating room. They will not be removed from the study as 
these AEs are not unacceptable.  
 
Subjects may withdraw consent at any time for any reason. A subject may be withdrawn 
by the investigator if enrollment into the study is determined inappropriate, the study plan 
is violated, or for administrative and/or other safety reasons.  
3.8 Primary Completion  
The expected primary completion date is 2 years after the study opens to accrual, as we 
expect that given the volume of bilateral mastectomies performed at our institution per 
week, we should be able to reach at least 150 participants in 2 years. 
3.9 Study Completion 
The expected study completion date is 2 years after the study opens to accrual. 


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• In patients with subarachnoid hemorrhage, due to risk of cerebral edema and 
cerebral infarction   
• In patients with active intravascular clotting  
• In patients with severe hypersensitivity reactions to tranexamic acid or any of the 
ingredients (4).  
 
Formulation, Appearance, Packaging, and Labeling 
Tranexamic Acid is available as a single-dose 1g vial that needs to be reconstituted in 
1ml of saline, to thus be 1000mg/ml. This 1g vial is readily available in the anesthesia 
cart in the operating room. This can then be added to 40cc saline to dilute it to 25mg/ml 
TXA solution. 20cc of this can then be infiltrated into the breast pocket, for a maximum 
exposure of 500mg of TXA to any one side  
Availability 
Tranexamic Acid is readily available at UCSF and stocked in most anesthesia carts in 
the operating room for perioperative administration in other surgical specialties.  
Side Effects 
The following side effects apply to intravenous systemic dosage of TXA, and may not 
necessarily apply to topical application.  
• 
Thromboembolic Risk 
• 
Seizures  
• 
Hypersensitivity Reactions  
• 
Visual Disturbances  
• 
Dizziness  
 
5 Treatment Plan 
5.1 Dosage and Administration 
Treatment will be administered in the operating room at the time of surgery. 20ml of 
25mg/ml solution of TXA will be infiltrated into one of the breast pockets and allowed to 
dwell in the pocket prior to closure. The other side will receive 20ml of plain 0.9% 
Saline. This will be the only administration of TXA for the duration of the study. 

  
5.2 Participant Registration 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a 
copy will be filed in the medical record.  The original will be kept on file with the study 
records.   
All participants consented to the study will be registered in OnCore®, the UCSF Helen 
Diller Family Comprehensive Cancer Center Clinical Trial Management System 
(CTMS).  The system is password protected and meets HIPAA requirements. 
 
6 Study Procedures and Schedule of Events 

6.1 Study Calendar 
The study-specific procedures and assessments are detailed in this section and outlined 
in the Study Calendar – 
   
 
Period/Procedure 
Screening Period 
 
Assessment Period3 
Study Day/Visit Day 
Pre-
operative 
period  
Day of 
Surgery 
During 
Surgery 
1-4 
weeks 
5-11 
weeks 
12 
weeks – 
1 year 
Informed consent1 
X 
 
 
 
 
 
Baseline conditions 
X 
 
 
 
 
 
TXA Exposure  
 
 
 
 
 
 
Right Breast 
 
 
 
 
 
 
Left Breast 
 
 
X 
 
 
 
Clinical procedures 
 
 
 
 
 
 
Physical exam 
 
X 
X 
X 
X 
X 
Vital signs 
 
X 
X 
X 
X 
X 
Medical history 
 
X 
 
 
 
 
AE assessment 
 
 
X 
X 
X 
X 
Outcomes 
assessment2  
 
 
 
 
X 
 
X 
 
X 
 
1 Informed consent can occur prior to screening window 
2 Outcomes from clinical exam including hematoma, seroma, infection 
3 Patients are scheduled for regular clinic visits up to one year after surgery. Study-
specific assessments and procedures will occur at these regularly scheduled visits. 
The exact timing of these visits varies by patient. If patients have multiple visits 
scheduled within these assessment windows, study-specific assessments and 
procedures may be performed at multiple visits on an optional basis

6.2 Participant Registration 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a 
copy will be filed in the medical record.  The original will be kept on file with the study 
records.   
All participants consented to the study will be registered in OnCore®, the UCSF Helen 
Diller Family Comprehensive Cancer Center Clinical Trial Management System 
(CTMS).  The system is password protected and meets HIPAA requirements. 
6.3 Schedule of Procedures and Assessments  
The study-specific assessments are detailed in this section. All on-site visit procedures 
are allowed a window of ± 10 days unless otherwise noted.  
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a 
copy will be filed in the medical record.  The original will be kept on file with the study 
records.   
Pre-operative period 
The pre-operative period will be defined as the time between a new patient visit to 
plastic surgery up to and including the day of surgery. After informed consent has been 
obtained and during this period of time, patients will be screened for participation in the 
study via review of their medical record. 
Day of surgery 
On the day of surgery, patients will undergo a condition-specific physical exam, have 
vital signs taken, and have their medical history reviewed. 
Screening period 
The screening period encompasses the pre-operative period up until the day of surgery. 
The allowable screening window is 6 months prior to the date of surgery. Patients who do 
not have surgery scheduled within 6 months of screening will be re-screened for eligibility 
within the screening window. 
Intraoperatively at time of bilateral mastectomy  
Tranexamic Acid is available as a sterile, single-dose 1g vial that needs to be 
reconstituted in 1ml of saline, to thus be 1000mg/ml. This 1g vial is readily available in 
the anesthesia cart in the operating room. Preoperatively, the surgery team will mix this 
into 40ml of 0.9% Normal Saline to thus produce a 25mg/ml TXA solution. 20ml of this 
will be passed onto the sterile surgical field for application to one breast pocket at the 
end of the case prior to closure. 20ml of 0.9% normal saline will also be passed onto the 
sterile surgical field for use on the control side.   
 

The surgeon will mix the TXA solution and pass onto the surgical field as outlined 
above. After the completion of the bilateral mastectomy, the plastic surgeon will perform 
their portion of the procedure. After obtaining hemostasis and irrigating as per standard 
practice, they shall not use any other hemostatic agents. Immediately prior to final 
closure, 20ml of 25mg/ml TXA solution shall be infiltrated into the right breast pocket. 
20ml of 0.9% normal saline shall be infiltrated into the left pocket. The sidedness of the 
TXA administration will be documented by the surgery team in our record but kept 
confidential from the surgery clinic staff to prevent bias at post-operative assessments. 
The solutions will be allowed to dwell, and JP drains will be kept off bulb suction until 
the end of the case. Post-procedure, each patient will be provided with standard post-
operative instructions which will include a chart to record drain outputs daily for the right 
and left sides.   
Post-Operative Clinic Visits 
Drain output will be assessed at each clinic visit to determine timing for removal. Drains 
will be removed per standard practice at our institution which is when they have 
produced < 30cc/day for at least 3 days.  
At each clinic visits up to one year after surgery, we will assess for clinical signs of 
hematoma, seroma, and ecchymoses. The number of post-operative clinic visits and 
their timings will vary by patient. Patients will be managed for hematoma and seroma as 
per standard procedure, whether with ultrasound, clinic aspiration, IR drain placement, 
or return to the operating room as deemed necessary by the senior surgeon.  
 
Optional Segments 
 
If patients have multiple visits within each block of the assessment period (1-4 weeks, 5-
11 weeks, and 12 week – 1 year), study-specific assessments and procedures may be 
performed.  
 
7 Reporting and Documentation of Results 
7.1 Statistical analysis 
We will compile an encrypted record of each patient and the study or control solution 
that was administered to each breast intraoperatively. We will then record data from the 
condition-specific physical examination at each post-operative clinic visit to track 
presence of hematoma, presence of seroma, laterality with worse bruising, amount of 
drain output prior to removal, and number of days with drain prior to removal. 
Demographic and surgical details will be collected for each patient. These will include 
patient demographics (i.e., age, BMI, race, ethnicity), clinical cancer characteristics (i.e., 
type of cancer, neoadjuvant chemo or radiation, adjuvant chemo or radiation), and post-
operative outcomes (i.e., hematoma, seroma, infection, return to the operating room, 
radiology aspiration or drain placement, clinic aspiration. Results will be analyzed 
comparing the outcomes of the TXA treated breasts with the Control (Saline) treated 
breasts using T test for continuous variables, and Chi Squared for categorical variables. 

Multivariate regression analysis will also be utilized to assess for the importance of 
various clinical and demographic factors (BMI, cancer laterality, etc.) on overall 
outcomes. For ecchymosis, the prevalence of worse ecchymosis with or without TXA 
will be reported as rated by the provider and patient at post operative visits.  
7.2 Safety Analysis 
Safety will be assessed by clinically assessing for signs of intolerance or irritation after 
administration of the TXA.  If there are any immediate adverse effects noted related to 
sensitivity reactions, the JP drain will be placed to suction and the TXA solution 
removed and washed out via infiltration of plain saline to the breast pocket. We will 
assess patients at each post-operative visit with condition-specific physical exam and 
history to make sure there are no other adverse effects noted. If any thrombotic 
complications are found with no other explanation, we will deem the study unsafe and 
stop the study.  
 
8 Study Management 
8.1 Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with 
GCP and all applicable regulatory requirements. Before initiating this study, the 
Investigator will have written and dated approval from the Institutional Review Board for 
the protocol, written informed consent form, subject recruitment materials, and any other 
written information to be provided to subjects before any protocol related procedures 
are performed on any subjects.   
8.2 Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) will be 
reviewed and approved by the UCSF IRB (UCSF Institutional Review Board).  Prior to 
obtaining IRB approval, the protocol must be approved by the Helen Diller Family 
Comprehensive Cancer Center Site Committee and by the Protocol Review and 
Monitoring Committee (PRMC).  The initial protocol and all protocol amendments must 
be approved by the IRB prior to implementation.  
8.3 Informed Consent 
All participants must be provided a consent form describing the study with sufficient 
information for each participant to make an informed decision regarding their 
participation.  Participants must sign the IRB-approved informed consent form prior to 
participation in any study specific procedure.  The participant must receive a copy of the 
signed and dated consent document.  The original signed copy of the consent 
document must be retained in the medical record or research file.  

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Any relevant additional information that pertains to a previously submitted IND safety 
report will be submitted to FDA as a Follow-up IND Safety Report without delay, as 
soon as the information is available (21 CFR 312.32(d)(2)).  
9.5 Follow-up of Adverse Events 
All participants who experience adverse events will be followed with appropriate medical 
management until resolved or stabilized, as determined by the investigator. For selected 
adverse events for which administration of the study drug/intervention was stopped, a 
re-challenge of the subject with the study drug/intervention may be conducted if 
considered both safe and ethical by the investigator. 
9.6 Adverse Events Monitoring 
Refer to the Data Safety Monitoring Plan, located in Appendix 1.
. 
 
 

10 References 
1. 
Serletti, J.M., et al., Breast reconstruction after breast cancer. Plast Reconstr 
Surg, 2011. 127(6): p. 124e-35e. 
2. 
Lovely, J.K., et al., Balancing venous thromboembolism and hematoma after 
breast surgery. Ann Surg Oncol, 2012. 19(10): p. 3230-5. 
3. 
Eustache, G. and L. Riffaud, Reducing blood loss in pediatric craniosynostosis 
surgery by use of tranexamic acid. Neurochirurgie, 2019. 65(5): p. 302-309. 
4. 
Eustache, G., et al., Importance of tranexamic acid in pediatric monosutural 
craniosynostosis surgery. J Neurosurg Pediatr, 2021: p. 1-7. 
5. 
Halanski, M.A., et al., The Efficacy of Amicar Versus Tranexamic Acid in 
Pediatric Spinal Deformity Surgery: A Prospective, Randomized, Double-Blinded 
Pilot Study. Spine Deform, 2014. 2(3): p. 191-197. 
6. 
Huerfano, E., et al., Use of Topical Tranexamic Acid Reduces Direct and Indirect 
Blood Loss and Transfusion Rates in Revision Total Hip Arthroplasty. HSS J, 
2020. 16(Suppl 2): p. 285-292. 
7. 
Husted, H., et al., Tranexamic acid reduces blood loss and blood transfusions in 
primary total hip arthroplasty: a prospective randomized double-blind study in 40 
patients. Acta Orthop Scand, 2003. 74(6): p. 665-9. 
8. 
Kochuba, A.L., et al., Prospective Study Assessing the Effect of Local Infiltration 
of Tranexamic Acid on Facelift Bleeding. Aesthet Surg J, 2021. 41(4): p. 391-
397. 
9. 
Martin, D.T., et al., Implementation of a Tranexamic Acid Protocol to Reduce 
Blood Loss During Cranial Vault Remodeling for Craniosynostosis. J Craniofac 
Surg, 2016. 27(6): p. 1527-31. 
10. 
McGuire, C., et al., Role of Tranexamic Acid in Reducing Intraoperative Blood 
Loss and Postoperative Edema and Ecchymosis in Primary Elective Rhinoplasty: 
A Systematic Review and Meta-analysis. JAMA Facial Plast Surg, 2019. 21(3): p. 
191-198. 
11. 
Orpen, N.M., et al., Tranexamic acid reduces early post-operative blood loss 
after total knee arthroplasty: a prospective randomised controlled trial of 29 
patients. Knee, 2006. 13(2): p. 106-10. 
12. 
Tzatzairis, T.K., et al., Intravenous vs Topical Tranexamic Acid in Total Knee 
Arthroplasty Without Tourniquet Application: A Randomized Controlled Study. J 
Arthroplasty, 2016. 31(11): p. 2465-2470. 
13. 
Weissler, J.M., et al., Intravenous Tranexamic Acid in Implant-Based Breast 
Reconstruction Safely Reduces Hematoma without Thromboembolic Events. 
Plast Reconstr Surg, 2020. 146(2): p. 238-245. 
14. 
Weissler, J.M., et al., Efficacy of Tranexamic Acid in Reducing Seroma and 
Hematoma Formation Following Reduction Mammaplasty. Aesthet Surg J, 2021. 
15. 
Ausen, K., et al., Topical moistening of mastectomy wounds with diluted 
tranexamic acid to reduce bleeding: randomized clinical trial. BJS Open, 2020. 
4(2): p. 216-224. 
16. 
2896366, F.D.L.R.I. Cyklokapron (Tranexamic Acid Injection). 2011  19 May 
2022]; Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019281s030lbl.pdf. 

17. 
Nielsen, R.E. and H. Husted, [Tranexamic acid reduces blood loss and the need 
of blood transfusion after knee arthroplasty]. Ugeskr Laeger, 2002. 164(3): p. 
326-9. 
18. 
Weissler, J.M., et al., Local Infiltration of Tranexamic Acid (TXA) in Liposuction: A 
Single-Surgeon Outcomes Analysis and Considerations for Minimizing 
Postoperative Donor Site Ecchymosis. Aesthet Surg J, 2021. 41(7): p. NP820-
NP828. 
19. 
Cristel, R.T., et al., Quantitative Analysis of Tranexamic Acid Effects on 
Ecchymosis in Rhinoplasty. Facial Plast Surg Aesthet Med, 2021. 
20. 
Collaborators, H.-I.T., Effects of a high-dose 24-h infusion of tranexamic acid on 
death and thromboembolic events in patients with acute gastrointestinal bleeding 
(HALT-IT): an international randomised, double-blind, placebo-controlled trial. 
Lancet, 2020. 395(10241): p. 1927-1936. 
 Appendix 1 (Single Site): Phase II or III Institutional Trial 
 
Data and Safety Monitoring Plan for a Phase II or III Institutional Trial 
 
1.         Oversight and Monitoring Plan 
 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and 
Safety Monitoring Committee (DSMC) is responsible for auditing data quality and 
participant safety for all HDFCCC institutional clinical trials.  A summary of DSMC 
activities for this trial includes:  
 
• Annual auditing (depending on trial accrual) 
• Review of serious adverse events 
• Minimum of biennial regulatory auditing 
 
2. 
Monitoring and Reporting Guidelines 
 
Investigators will conduct a continuous review of data and participant safety at 
monthly site committee meetings where the results of each participant’s 
treatment are discussed and documented in the site committee minutes.   
 

All institutional Phase II and III therapeutic trials are audited on an annual basis, 
with all data from 20% percent of the enrolled participants audited by the DSMC 
Monitor/Auditor.   
 
The assigned DSMC Monitor/Auditor will review no more than a total of 10 
participant charts during the course of auditing this trial. DSMC Monitor/Auditors 
will send a follow-up report to the study team within 20 business days after the 
auditing visit is complete for the PI and the study team to resolve all action items 
from this report within 20 business days.  An abbreviated regulatory review (i.e., 
reviewing protocol and consent versions, SAEs, PVs, DOA logs, 1572 forms, 
etc.) will occur at each participant monitoring review; however, a full regulatory 
review will occur on a biennially basis by the DSMC for regulatory compliance. 
 
Auditing of all enrolled participants in these trials will be complete after 20% of 
enrolled participants have been audited through five cycles of treatment.  
However, regulatory reviews of the trial, safety reviews (i.e., Serious Adverse 
Event (SAE) reviews and Protocol Violation (PV) reviews), and audit/inspection 
preparation (as applicable) will continue until the trial is closed by the IRB.   
 
3. 
Review and Oversight Requirements 
 
 
3.1 
Adverse Event Monitoring  
 
All Grade 3-5 adverse events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the use of the 
investigational agent(s) or study procedure, will be entered into OnCore®, 
UCSF’s Clinical Trial Management System.   
 
Adverse events are graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) as developed and revised by the Common Therapy 
Evaluation Program (CTEP) of the National Cancer Institute.  Adverse events are 
further given an assignment of attribution or relationship to investigational agent 
or study procedure.  Attribution categories are: 
 

• 
Definite – clearly related to the investigational agent(s) or study 
procedure. 
• 
Probable – likely related to the investigational agent(s) or study 
procedure. 
• 
Possible – may be related to the investigational agent(s) or study 
procedure. 
• 
Unrelated –clearly not related to the investigational agent(s) or study 
procedure. 
 
All Grade 3-5 adverse events entered into OnCore will be reviewed on a monthly 
basis at the Site Committee meetings.  The Site Committee will review and 
discuss the selected toxicity, the toxicity grade, and attribution assignment. 
 
3.2 
Serious Adverse Event Reporting  
 
By definition, an adverse event is defined as a serious adverse event (SAE) 
according to the following criteria: 
 
 
• 
Death, 
• 
Life-threatening adverse experience*, 
• 
Inpatient hospitalization or prolongation of existing hospitalization, 
• 
Persistent or significant disability/incapacity, 
• 
Congenital anomaly/birth defect, or cancer, or 
• 
Any other experience that suggests a significant hazard, contraindication, 
side effect or precaution that may require medical or surgical intervention to 
prevent one of the outcomes listed above, 
• 
Event that changes the risk/benefit ratio of the study.  
* A life-threatening adverse experience is any AE that places the patient or 
subject, in the view of the investigator, at immediate risk of death from the 
reaction as it occurred, i.e., it does not include a reaction that, had it occurred 
in a more severe form, might have caused death. 
 
Serious adverse event reporting will be in accordance with all IRB regulations. 
For trials conducted under an investigational new drug (IND) application, the SAE 

will be reported in accordance with Code of Federal Regulation Title 21 Part 
312.32 and will be reported on a Med Watch form.   
 
UCSF IRB website for guidance in reporting serious adverse events: 
https://irb.ucsf.edu/adverse-event  
 
Med Watch forms and information: 
www.fda.gov/medwatch/getforms.htm 
 
All serious adverse events are entered into OnCore, as well as submitted to the 
IRB (per IRB guidelines).  The SAEs are reviewed and monitored by the Data 
and Safety Monitoring Committee on an ongoing basis and discussed at DSMC 
meetings, which take place every six weeks.  The date the SAE is sent to all 
required reporting agencies will be documented in OnCore®.  
 
If the SAE involves a subject death, and is determined to be possibly, probably or 
definitely related to the investigational drug or any research related procedure, 
the event must be reported to the DSMC Chair (or Vice Chair) and DSMC 
Director within one business day.   
 
3.3        Review of Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate 
reported in the Investigator Brochure or package insert) is noted in the study, the 
Principal Investigator will notify the DSMC via report at the time the increased 
rate is identified.  The report will indicate if the incidence of adverse events 
observed in the study is above the range stated in the Investigator Brochure or 
package insert. 
 
If at any time the Investigator voluntarily holds enrollment or stops the study due 
to safety issues, the DSMC Chair (or Vice Chair) and the DSMC Director must be 
notified within one business day and the IRB must be notified as per IRB 
reporting regulations. 
 

Data and Safety Monitoring Committee Contacts: 
 
  Katie Kelley, MD (DSMC 
Chair) 
 
  
  
 
  
 
  UCSF HDFCCC 
  San Francisco, CA 94158 
 
 
 
 
 
John McAdams (DSMC Director)  
 
 
 
UCSF HDFCCC 
San Francisco, CA 94158