Effect of Tranexamic Acid on Postoperative Bleeding Following Sinus and Nasal Surgery
Phase: PHASE4
Conditions: Chronic Sinusitis, Nasal Obstruction, Turbinate; Hypertrophy Mucous Membrane, Deviated Nasal Septum - Congenital, Deviated Nasal Septum Acquired
Sponsor: Stanford University

 
Effect of Tranexamic Acid on Postoperative Bleeding Following 
Sinus and Nasal Surgery 
Study Protocol and Statistical Analysis Plan 
NCT04754230 
February 10, 2021 
1. 
PURPOSE OF THE STUDY 
a. 
Brief Summary 
The purpose of the research is to assess the effectiveness of a medication called 
tranexamic acid (TXA) when given intraoperatively to reduce bleeding postoperatively 
after sinonasal surgery (e.g. septoplasty, endoscopic sinus surgery). This medication has 
already been shown to decrease blood loss during surgery, but the implications for 
bleeding after surgery are unclear. Any impact on postoperative bleeding from the nose 
will be assessed over the first 7 days following surgery leading up to the first 
postoperative clinic visit. 
b. 
Objectives 
We hope to learn whether use of the tranexamic acid (TXA) lowers the 
amount of bleeding after surgery as well as the need for repeat evaluation and additional 
intervention including nasal packing, cautery, and return trips to the OR. If the 
medication proves effective in doing so, this knowledge will help provide a rationale for 
sinus surgeons to routinely use this medication intraoperatively to reduce postoperative 
bleeding, thereby improving the patient experience and reducing use of hospital 
resources, both in terms of physical and human capital. 
c. 
Rationale for Research in Humans 
This study evaluates the clinical effect of tranexamic acid (TXA) on bleeding followed 
sinonasal surgery. As a clinical study, it necessarily involves the use of human subjects to 
assess the impact. The study will also evaluate the patient experience and the impression 
that patients have of their own bleeding following these procedures. 
2. 
STUDY PROCEDURES 
a. 
Procedures 
After a patient in the outpatient clinic has been recommended for and agreed to sinonasal 
surgery (e.g. septoplasty, turbinate reduction, endoscopic sinus surgery), they will then be 
eligible for screening for the study. Patients will only be informed of the existence of the 

February 10, 2021 
 
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study in a clinical context if they meet the screening requirements. Screening may occur 
either at the preoperative visit that is part of the standard of care, or on the morning of 
surgery during the surgical consent process if the patient decided to schedule surgery 
remotely without a preoperative visit. For any patients who have their pre-op visit via 
telehealth instead of in-person, it will still be brought up in the clinical context of that 
pre- operative visit. If a patient is interested, the patient will receive more information 
regarding the study details, and if the patient wishes to participate after a full informed 
consent process, written consent will be obtained. Patients will need to be able to provide 
voluntary consent; those who cannot will be excluded. Patients will be excluded if they 
under 18 years of age, are pregnant or may become pregnant by time of surgery, are 
prisoners, are international participants, are unable to provide consent, or are non-English 
speaking. Patients will also be excluded if they have known pro-thrombotic clotting 
disorders. Other patients that are not specifically targeted but will not necessarily be 
excluded include employees and students, as long as they are able to provide voluntary 
consent.  Once a patient has had all questions answered and has voluntarily enrolled in 
the study, the patient will be provided with a bleeding diary template to record the 
postoperative experience which include VAS evaluation postoperative bleeding and 
number of gauze changes per day. They will use this diary template daily postoperatively.  
Patients will be randomized to receive either the study medication (TXA with saline 
infusion) or not (saline infusion alone). The surgeon will be blinded to this selection. The 
anesthesiologist will not be blinded. However, the patient's participation in the study will 
be announced during the surgical time out, and it will be announced that the attending 
surgeon is blinded to the patient's participation. The patient will undergo general 
anesthesia and undergo their sinonasal surgery as routine. The study intervention will 
occur 15 minutes before completion of the surgery. At this time, a 1,000 mg IV dose of 
tranexamic acid will be added to the saline infusion by the anesthesiologist for patients 
randomized to the intervention. Patients randomized to placebo will continue to receive 
their routine infusion of normal saline, which is administered throughout surgery. The 
anesthesiologist will be asked only to state 'study medication administered" at the time of 
administration, whether the infusion consists of saline alone or with the addition of TXA. 
This will be the only way in which the two study arms differ.  To standardize patient 
management, packing materials (e.g. nasopore, surgical, Floseal) will not be used at the 
end of a surgery. However, if a patient experiencing clinically concerning bleeding at the 
termination of surgery that requires use of these materials (or the clinically indicated use 
of a dose of TXA), they will be unblinded, removed from the protocol, and managed 
accordingly. Patient safety will always take priority.  After reversal of anesthesia and 
extubation, patients will be transported to recovery as per standard of care. They will be 
discharged home when meeting routine post-anesthesia criteria (tolerating oral intake, 
control of nausea, control of pain, etc).  After discharge home and through the following 
week leading up to their postoperative visit, all patients will fill out the diary template 
outlined above to characterize their daily postoperative bleeding.    Patients will then 
follow up for their first postoperative clinic visit one week after surgery which is the 
standard of care. They will turn in their postoperative bleeding diary entries at this time. 
Their active obligation at this point is over, but they will always have the right to have 
their data removed from analysis if they wish to withdraw. They will not be contacted for 
research purposes after this point in regards to this specific study, but will continue to 
follow up clinically as per standard of care. They will have no clinic visits exclusively for 

February 10, 2021 
 
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research purposes; the only visits will be part of the standard of care.  Surgical residents 
will maintain a list of study patients on whom they are called to evaluate for 
postoperative bleeding in the recovery unit. They will be blinded to whether the patient 
received the study medication or placebo. Records (i.e. via STARR) will be queried to 
determine the frequency with which patients in each group call the clinic or answering 
service with bleeding- related concerns. Records of further intervention (nasal packing, 
cautery, return to OR) will also be gathered. These outcomes will be used to determine 
the difference between groups. Patients will have received the standard of care for 
postoperative epistaxis in all these scenarios, identical to patients who are not enrolled in 
the study.  The primary outcome is the patient-reported VAS bleeding score after surgery. 
This methodology has been used by other published work to assess the impact of agents 
used at the end of procedures to reduce the rate of postoperative bleeding after sinonasal 
surgery (https://journals.sagepub.com/doi/10.1016/j.otohns.2009.06.078). Using their 
results as a reference, we may expect that the VAS score on postoperative day one may 
drop from a 4 to a 2. Assuming an SD of 1.6-1.8 for the purpose of estimations, we would 
need 24-28 total cases to detect the effect size of 2 in VAS if using 1:1 ratio with 80% 
power.  The secondary outcome is the frequency with which the service is requested to 
evaluate patients in the recovery unit for postoperative bleeding concerns after sinonasal 
surgeries. Anecdotal feedback from the resident service suggests that they are requested 
to evaluate roughly 30% of these patients. With the hypothesis that the TXA could reduce 
the frequency by roughly half to 15%, we will require 118 patients in each group (total 
N=236) to achieve 80% power to detect a difference between the two group proportions 
of 15% (with 30% in placebo, 15% in TXA group). This estimate uses two sided Z-test 
while assuming type I error=0.05. 
b. 
Procedure Risks 
These procedures involve the delivery of routine standard of care in all facets of sinonasal 
surgery with the addition of a single medication intervention to be delivered 
intraoperatively while under the direct care and supervision of the anesthesiology service. 
Any unexpected hemodynamic or clinical side effects can therefore be immediately 
assessed and addressed. The planned medication dose is based on previous studies and 
has been extremely well tolerated during studies evaluating its use in endoscopic sinus 
surgery to assess the effect on intraoperative bleeding. Higher doses have been used for 
other indications including orthopedic surgery, however we plan to utilize this lower dose 
with a proven safety record. 
c. 
Use of Deception in the Study 
N/A 
d. 
Use of Audio and Video Recordings 
N/A 
e. 
Alternative Procedures or Courses of Treatment 
The alternative is not to participate and to receive the routine standard of care with no 
change in risks. This involves observation after surgery with traditional management of 
epistaxis if it occurs (oxymetazoline nasal spray and pressure, Floseal hemostatic matrix, 

February 10, 2021 
 
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formal nasal packing as required). These will still all be available for patients, as their 
utilization is one of the endpoints of the study. No care or alternative medications are 
being withheld in order to participate in this study. This is an additional intervention to 
the routine standard of care. All patients will continue to be treated as clinically indicated. 
f. 
Will it be possible to continue the more (most) appropriate therapy for the 
participant(s) after the conclusion of the study? 
Patients will receive the appropriate standard of care both during and after the conclusion 
of the study. Nothing will change in regards to their normal clinical management by 
participating in the study. 
g. 
Study Endpoint(s) 
Patients data will be gathered for one week postoperatively and their direct participation 
will end at the first clinical visit one week after surgery (their data will still be analyzed 
after that time). The primary endpoint is the patient VAS assessment of postoperative 
bleeding over the first week, and the patient report of gauze usage over the first week. 
Secondary endpoints to be evaluated will include the proportion of patient in recovery on 
whom the nurses contact the on-call resident for assessment with postoperative bleeding, 
the need for interventions to address postoperative bleeding (cautery, nasal packing, 
return to OR), and frequency of patient calls to clinic after discharge home with bleeding 
concerns.  If during interim data analysis a significant difference in postoperative 
bleeding is noted without an increase in adverse events, discussion could be had with the 
IRB over developing a new standard of care, however we would anticipate continuing 
with the standard of care through the end of the study. 
3. 
BACKGROUND  
a. 
Past Experimental and/or Clinical Findings 
The rationale for this study is based on the findings from other groups that have 
consistently demonstrated a reduction in intraoperative bleeding with the use of 
tranexamic acid (TXA) without any significant adverse events. A systematic review and 
meta- analysis of 5 RCTs including 192 patients receiving a variety of routes of 
administration TXA (incuding IV, oral, and topical) demonstrated a mean decrease in 
operative blood loss and resulting improved surgical field quality without any difference 
in adverse events.(1) A more recent meta-analysis came to the same conclusions by 
evaluating 11 RCTs.(2) A study examining only IV TXA given at induction of anesthesia 
demonstrated a significant reduction in bleeding with no incidence of thrombosis in either 
group, one of the main theoretic concerns of TXA. (3) One patient in the study required 
intervention for epistaxis, and this patient was in the placebo group. A recent publication 
in the Laryngoscope evaluated 7 RCTs with a total of 562 patients and found reduced 
blood loss with TXA versus placebo with no difference in hemodynamics, coagulation 
profiles, emesis, or thrombotic events.(4) Numerous additional studies have proven the 
benefit of topical and IV TXA used intraoperatively to reduce intraoperative blood loss, 
with a recent randomized clinical trial demonstrating no increase in MAP, HR, PT, or 
PTT. (5)  Given the robustness of these findings but without clear evidence to date on 
postoperative bleeding, nor the resource utilization spent on evaluation by the surgical 

February 10, 2021 
 
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service in the recovery unit, a Cochrane protocol was developed in 2017. (6) Among the 
secondary outcomes of the protocol includes complications and postoperative bleeding, 
however the protocol has not been published and no studies since that time have 
answered this particular question.   
 
1. Pundir V, Pundir J, Georgalas C, Fokkens WJ. Role of tranexamic acid in endoscopic 
sinus surgery - A systematic review and meta-analysis. Rhinology. 2013;51(4):291–7.  
2. Ping WD, Zhao QM, Sun HF, Lu HS, Li F. Role of tranexamic acid in nasal surgery: A 
systemic review and meta-analysis of randomized control trial. Medicine (Baltimore). 
2019;98(16):e15202.  
3. Alimian M, Mohseni M. The effect of intravenous tranexamic acid on blood loss and 
surgical field quality during endoscopic sinus surgery: A placebo-controlled clinical trial. 
J Clin Anesth [Internet]. 2011;23(8):611–5. Available from: 
http://dx.doi.org/10.1016/j.jclinane.2011.03.004  
4. Kim DH, Kim S, Kang H, Jin HJ, Hwang SH. Efficacy of tranexamic acid on operative 
bleeding in endoscopic sinus surgery: A meta-analysis and systematic review. 
Laryngoscope. 2019;129(4):800–7.  
5. El‐Din El‐Ozairy HS, Mady OM, Tawfik GM, Elhennawy AM, Teaima AA, Ebied A, 
Huy NT. Outcomes of combined use of topical and intravenous tranexamic acid on 
surgical field quality during functional endoscopic sinus surgery: A randomized 
controlled trial. Head & Neck. 2021, early view. 
6. Ravesloot MJL, Lourijsen E, Avdeeva K, Pundir V, Fokkens W. Tranexamic acid for 
the reduction of bleeding during functional endoscopic sinus surgery. Cochrane Database 
Syst Rev. 2017;2017(11). 
b. 
Findings from Past Animal Experiments 
N/A 
4. 
RADIOISOTOPES OR RADIATION MACHINES 
N/A 
5. 
DEVICES USED IN THE STUDY 
N/A 
6. 
DRUGS, BIOLOGICS, REAGENTS, OR CHEMICALS USED IN THE STUDY 
a. 
Investigational Drugs, Biologics, Reagents, or Chemicals 
N/A 
b. 
Commercial Drugs, Biologics, Reagents, or Chemicals 
Commercial Product 1 
Name: 
Tranexamic acid 
Dosage: 
1000 mg 

February 10, 2021 
 
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7. 
DISINFECTION PROCEDURES FOR MEDICAL EQUIPMENT USED ON BOTH HUMANS AND 
ANIMALS 
N/A 
 
8. 
PARTICIPANT POPULATION 
a. 
Planned Enrollment 
All patients will be recruited at Stanford Sinus Center. Given the expected number of 
patients to power the study based on the calculations listed in section 2a, this will include 
approximately 250 total patients. To be included, patients will have to be scheduled for 
sinonasal surgery, as this is the population of interest. While students and employees will 
not be specifically targeted, they also will not be specifically excluded. Patients with 
surgery for sinonasal cancer will be excluded as this study will focus on routine sinonasal 
surgery for nasal obstruction and/or chronic rhinosinusitis. 
b. 
Age, Gender, and Ethnic Background 
Patients will include both men and women 18 years of age or older from all ethnicities 
that present to Stanford outpatient clinics. 
c. 
Vulnerable Populations 
Children, pregnant women, homeless, and decisional impaired patients will be excluded 
from the study. Students, employees, and economically and educationally disadvantaged 
patients will be offered the opportunity to participate in the study, however it will be 
made clear that if they choose not to participate they will otherwise still receive the 
identical standard of care. There will be no pressure to participate given the high volume 
of patients that are scheduled for surgery through the sinus center. 
d. 
Rationale for Exclusion of Certain Populations 
This study will only be implemented at the adult hospital. Children do not receive 
surgical care at the adult hospital, but rather only at LPCH. As such, by necessity, they 
will be excluded. 
e. 
Stanford Populations 
Laboratory personnel, employees, and students are eligible for the study, but will not be 
specifically targeted. All those who have been scheduled for sinonasal surgery who do 
not meet the exclusion criteria (pregnant women, children, prisoners, international, etc) 
will be offered participation in the study. No participants will receive compensation. 
f. 
Healthy Volunteers 
N/A - all patients will have a diagnosis code requiring sinus or nasal surgery 

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g. 
Recruitment Details 
Patients seen in the outpatient clinic and offered to schedule elective sinus or nasal 
surgery will automatically be screened for inclusion into the study. Advertisements will 
not be used; rather the clinician will inform the patient of the research trial and if the 
patient expresses interest a member of the research team will discuss the details of the 
trial with the patient, answer further questions, and obtain consent. 
h. 
Eligibility Criteria 
i. 
Inclusion Criteria 
Scheduled to undergo elective sinus or nasal surgery (e.g. septoplasty, inferior 
turbinate reduction, endoscopic sinus surgery) 
Age 18 or greater 
English-speaking 
Able to provide consent 
ii. 
Exclusion Criteria 
Minors (age<18) 
Pregnant or may become pregnant by time of surgery 
Prisoners 
Non-English speaking 
Foreign citizens 
Unable to provide consent 
Known pro-thrombotic coagulation disorders 
Active intranasal drug use (e.g. cocaine) 
Surgery is for a sinonasal tumor or other sinus pathology not described in inclusion 
criteria 
Enrollment is in conflict with existing study participation 
i. 
Screening Procedures 
Patients will be screened in the outpatient clinic for inclusion in the study once electing to 
schedule sinonasal surgery. Their past medical history will be obtained at this time to 
determine eligibility. If the patient is pregnant or has a reported history of a pro-
thrombotic coagulopathy, they will be excluded from the study. Medication history will 
also be evaluated to determine whether a patient is on blood thinners to provide context 
to outcomes for subset analysis. Standard of care will be used in regards to medication 
management before and after surgery; there will be no alteration in medication 
management as a result of inclusion in the study. 
j. 
Participation in Multiple Protocols 
The patient may potentially be enrolled in other unrelated study protocols. They will be 
asked about participation in other studies at the time of enrollment in this study to 
confirm there is no conflict by enrolling in this study. 

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k. 
Payments to Participants 
N/A 
l. 
Costs to Participants 
Only the costs of routine medical care associated with the surgery and postoperative care 
will be charged to the patient, as is routine. There will be no additional costs to the 
patient by participating in this study. 
m. 
Planned Duration of the Study 
Once enrollment begins, the expected duration of the study is expected to be 6-12 months 
depending on speed of enrollment. Screening will take roughly 10 minutes during the 
preoperative clinic visit. Active participation in the study will last from the day of surgery 
to the first scheduled clinical visit one week later. Analysis of patient data will be 
performed quarterly. 
9. 
RISKS 
a. 
Potential Risks 
i. 
Investigational devices 
N/A 
ii. 
Investigational drugs 
N/A 
iii. 
Commercially available drugs, biologics, reagents or chemicals 
Tranexamic acid: 
Safety: Higher total IV doses (eg, ≥50 mg/kg), such as those given perioperatively, 
may be associated with an increased risk of seizures; lower doses (eg, 1 or 2 g given 
in the first 8 hours of trauma) do not appear to increase the risk of seizure or venous 
thromboembolism (CRASH-3 Trial Collaborators 2019; Fillingham 2018a; Lecker 
2016; Myles 2017; Sigaut 2014). 
 
Of note, this study will utilize a single 1g dose toward the end of surgery, therefore 
no risk of these issues would be expected in our study. 
 
Less common side effects such as low blood pressure, nausea and vomiting are also 
more often seen at the high dose if medication, but may be possible at the low dose as 
well. 
iv. 
Procedures 
Risks of sinus and nasal surgery are reviewed with every patient during informed 
consent for the surgical procedure itself in the outpatient setting. These risks remain 
the same regardless of participation in the study. These risks include infection, 
bleeding, damage to surrounding structures such as the orbit or intracranial cavity, 
persistent olfactory dysfunction, septal hematoma/perforation, hypoesthesia of 

February 10, 2021 
 
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dentition and/or face, need for revision surgery to achieve optimal result, and risks 
associated with general anesthesia. Patients must accept these risks before being 
scheduled for elective surgery. 
v. 
Radioisotopes/radiation-producing machines 
N/A 
vi. 
Physical well-being 
The risks to physical well-being are those associated with underlying disease process 
and indicated surgery as above. Participation in the study does not alter these risks. 
vii. 
Psychological well-being 
The risks to psychological well-being are those associated with underlying disease 
process and indicated surgery as above. Participation in the study does not alter these 
risks. 
viii. 
Economic well-being 
The risks to economic well-being are those associated with underlying disease 
process and indicated surgery as above. Participation in the study does not alter these 
risks. 
ix. 
Social well-being 
The risks to social well-being are those associated with underlying disease process 
and indicated surgery as above. Participation in the study does not alter these risks. 
x. 
Overall evaluation of risk 
Low 
b. 
International Research Risk Procedures 
N/A 
c. 
Procedures to Minimize Risk 
The intervention medication will be administered in the operating room under the 
supervision of the anesthesia team. Any unexpected side effects will be identified and 
addressed at that time. As a matter of routine, patients are watched in the recovery unit 
after surgery for a period of approximately two hours. The half-life of the IV formulation 
of tranexamic acid is 2 hours, and so any side-effects should be noted prior to discharge 
home. 
To reduce the risk of data breach, data will be coded after the completion of the patient's 
participation, which will terminate at the first clinical follow-up visit one week after 
surgery, at which time they will submit their bleeding journal template. Data will be 
stored only on a encrypted laptop, and if sharing is required will be done through 
Stanford-sponsored secure data sharing platforms such as Box. 

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d. 
Study Conclusion 
As above, active individual patient participation terminates at one week postoperatively. 
All the data necessary for analysis will have been gathered at this time. This data will still 
be analyzed along with the remainder of the patients until the time of study completion, 
which is expected to be 6-9 months later once an adequate number of patients have been 
recruited. 
As above, patients will continue to receive the routine standard of care during this study. 
Epistaxis is expected after sinonasal surgery and is addressed in a variety of ways 
(observation, holding pressure, nasal sprays, nasal packing, return to OR). The purpose of 
this study is to determine whether this inherent risk of bleeding can be reduced. All of 
these interventions are still available and will be used as clinically indicated. 
e. 
Data Safety Monitoring Plan (DSMC) 
i. 
Data and/or events subject to review 
Data that will be collected include study-related adverse events (e.g. thrombosis, 
nausea requiring overnight admission) and any serious adverse events (e.g. death), 
suspected serious adverse reactions, and unanticipated problems. Outcomes data will 
be analyzed every 3 months to assess progress toward study endpoints and to ensure 
no unanticipated risks of study participation. 
ii. 
Person(s) responsible for Data and Safety Monitoring 
Dr. Zara Patel (PD) 
iii. 
Frequency of DSMB meetings 
Meetings will occur quarterly. If deemed necessary by the IRB, written 
recommendations will be submitted after each meeting, to include plans to continue 
the study as designed, continue with modification, temporarily suspend, or terminate. 
iv. 
Specific triggers or stopping rules 
The study will end when recruitment targets are reached or if interim data analysis 
demonstrates a statistically significant difference in endpoints between groups. If 
Suspected Unexpected Serious Adverse Reactions or Unanticipated Problems (UPs) 
are encountered, the study will be halted and possibly terminated early if the issue 
cannot be resolved. 
v. 
DSMB Reporting 
The outcome of the review will be disseminated to the co-investigators and the IRB. 
vi. 
Will the Protocol Director be the only monitoring entity? (Y/N) 
Yes 
vii. 
Will a board, committee, or safety monitor be responsible for study monitoring? 
(Y/N) 
No 

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f. 
Risks to Special Populations 
N/A 
10. 
BENEFITS 
Participants in the study may receive direct benefit if the administration of tranexamic acid does 
indeed reduce postoperative bleeding, and assuming the participant receives tranexamic acid 
rather than placebo. Because this is not yet proven, and this study is designed to evaluate this, this 
is a potential benefit and not a certain benefit. Furthermore, if the patient receives placebo, they 
will receive no benefit, and will have received the routine standard of care. 
 
If the data gathered from the study is able to show a benefit without additional risks with the 
administration of a dose of tranexamic acid, then future patients may benefit from this 
knowledge with a change in the routine standard of care. Given that this type of surgery is one 
of the most common in the United States, many future patients may have a more favorable 
postoperative course if the volume of bleeding is able to be reduced effectively. 
11. 
PRIVACY AND CONFIDENTIALITY 
All participant information and specimens are handled in compliance with the Health Insurance 
Portability and Accountability Act (HIPAA) and privacy policies of Stanford University, Stanford 
Health Care, and Stanford Children’s Health.