Tranexamic Acid in Radical Resection and Endoprosthetic Reconstruction: A Randomized Controlled Trial
Phase: PHASE4
Conditions: Musculoskeletal Cancer, Sarcoma,Soft Tissue
Sponsor: University of Kansas Medical Center

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NCT04347122 
Tranexamic Acid in Radical Resection and Endoprosthetic Reconstruction Protocol 
Dec 17, 2019 
 
 

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University of Kansas Medical Center   
RESEARCH PROTOCOL INVOLVING HUMAN SUBJECTS  TEMPLATE 
WITH GUIDANCE  
  
Version date: 12/17/2019  
Principal Investigator: Kyle Sweeney MD, Assistant Professor of Orthopaedic Surgery    
Study Title: Tranexamic Acid in Radical Resection and Endoprosthetic Reconstruction: A Randomized 
Controlled Trial  
Co- Investigator(s): Howard Rosenthal MD, Kimberly Templeton MD, Jacob Birlingmair MD   
 
  
I.  
Purpose, Background and Rationale A. Aim and Hypotheses   
Resection of bony and soft tissue tumors with endoprosthetic reconstruction presents a 
significant risk of perioperative blood loss requiring transfusion.  As transfusions are 
known to have inherent risks, a goal of therapy is to minimize perioperative blood loss.  
Tranexamic acid (TXA) is an antifibrinolytic that is commonly used to reduce blood loss in 
orthopaedic procedures, most often arthroplasty.  The safety (even in patients with 
significant comorbidities) and efficacy of TXA in joint arthroplasty is well documented in 
the literature. There is, however, a dearth of literature exploring the safety and efficacy of 
TXA in musculoskeletal oncologic patients.    
  
The aim of this study is to determine in a randomized controlled fashion if there is any 
difference in perioperative blood loss and blood transfusion rates when tranexamic acid is 
used compared to when it is not used in patients undergoing radical resection of bone 
and soft tissue sarcomas with endoprosthetic reconstruction.  Hypotheses: (1) TXA will 
decrease perioperative blood loss.  (2) TXA will decrease blood transfusion rates.  (3) TXA 
will decrease post-operative surgical drain output.  
  
B. Background and Significance  
Study Significance: The large bony and soft tissue tumor resections performed in 
musculoskeletal oncologic patients presents the potential for significant blood loss.  With 
basic arthroplasty being associated with significant intraoperative and postoperative 
blood loss often necessitating blood transfusion1, larger bony resections with the use of 
endoprostheses presents an even higher risk2.  Transfusions themselves are not without 
known complications. Examples include infection, hemolytic transfusion reaction, and 
increased short-term mortality1,3. Tranexamic acid (TXA), a synthetic analog of lysine, is 
an antifibrinolytic that is used to reduce blood loss. TXA works by blocking the lysine 
binding sites on plasminogen4. Perioperative use of TXA has been shown to decrease 
intraoperative and postoperative blood loss and decrease transfusion rates in both total 
knee arthroplasty and total hip arthroplasty5-15. It has also been shown to result in higher 
postoperative hemoglobin13. TXA also has been shown to decrease postoperative pain, 
swelling, length of hospital stay, and result in higher patient satisfaction 16. The proposed 
research is intended to show if any correlation exists between administration of TXA or 
not to musculoskeletal oncology patients undergoing endoprosthetic reconstruction and 
perioperative blood loss and blood transfusion rates.  The results of this study are 

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important because it will serve to fill the void in the current literature as there is no 
current literature available that has studied TXA administration in this specific patient 
population.   
  
There have been several papers written with regards to the safety of TXA in high risk 
patients (i.e. previous PE/VTE event).21,22 Whiting et al showed that in high risk patients 
(defined as American Society of Anesthesiologists score of III or IV) , TXA was not 
associated with an increase in symptomatic thromboembolic events and was associated 
with a decrease in transfusion rates.22  Sabbag et al showed that patients with a history 
of VTE had a low risk of recurrent VTE (2%) after contemporary total hip arthroplasty and 
total hip arthroplasty, and that rate was not increased with the use of IV TXA.21  
  
Literature Review  
1. Sabatini L, Atzori F, Revello S, Scotti L, Debiasi F, Massè A. Intravenous use of 
tranexamic acid reduces postoperative blood loss in total knee arthroplasty. Arch 
Orthop Trauma Surg. 2014 Sep 3;PubMed PMID: 25179896.   
2. Borisov DB, Iudin SV, Tiuriapin AA, Kapinos AA, Vyl'iurov IV, Kazakevich EV. 
[Prevention and treatment of anemia during endoprosthetic replacement of large 
joints]. Anesteziol Reanimatol. 2010 Mar-Apr;PubMed PMID: 20524332.   
3. Wei W, Wei B. Comparison of Topical and Intravenous Tranexamic Acid on Blood Loss 
and Transfusion Rates in Total Hip Arthroplasty. J Arthroplasty. 2014 Jul 30;PubMed 
PMID: 25155138.   
4. Aguilera X, Martinez-Zapata MJ, Bosch A, Urrútia G, González JC, Jordan M, Gich I, 
Maymó RM, Martínez N, Monllau JC, Celaya F, Fernández JA. Efficacy and safety of 
fibrin glue and tranexamic acid to prevent postoperative blood loss in total knee 
arthroplasty: a randomized controlled clinical trial. J Bone Joint Surg Am. 2013 Nov 
20;95(22):2001-7. PubMed PMID: 24257657.   
5. Bidolegui F, Arce G, Lugones A, Pereira S, Vindver G. Tranexamic Acid Reduces Blood  
Loss and Transfusion in Patients Undergoing Total Knee Arthroplasty without 
Tourniquet: A Prospective Randomized Controlled Trial. Open Orthop J. 2014;8:2504. 
PubMed PMID: 25132872; PubMed Central PMCID: PMC4133924.   
6. Samujh C, Falls TD, Wessel R, Smith L, Malkani AL. Decreased blood transfusion 
following revision total knee arthroplasty using tranexamic Acid. J Arthroplasty. 2014 
Sep;29(9 Suppl):182-5. PubMed PMID: 25015759.   
7. Levine BR, Haughom BD, Belkin MN, Goldstein ZH. Weighted versus uniform dose of 
tranexamic Acid in patients undergoing primary, elective knee arthroplasty: a 
prospective randomized controlled trial. J Arthroplasty. 2014 Sep;29(9 Suppl):186-8. 
PubMed PMID: 24997651.   
8. Soni A, Saini R, Gulati A, Paul R, Bhatty S, Rajoli SR. Comparison between 
intravenous and intra-articular regimens of tranexamic acid in reducing blood loss 
during total knee arthroplasty. J Arthroplasty. 2014 Aug;29(8):1525-7. PubMed PMID: 
24814890.   
9. Yue C, Kang P, Yang P, Xie J, Pei F. Topical Application of Tranexamic Acid in Primary 
Total Hip Arthroplasty: A Randomized Double-Blind Controlled Trial. J Arthroplasty. 
2014 Mar 29;PubMed PMID: 24793893.  
10. Chang CH, Chang Y, Chen DW, Ueng SW, Lee MS. Topical tranexamic acid reduces 
blood loss and transfusion rates associated with primary total hip arthroplasty. Clin 

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Orthop Relat Res. 2014 May;472(5):1552-7. PubMed PMID: 24385043; PubMed 
Central PMCID: PMC3971210.    
11. Wind TC, Barfield WR, Moskal JT. The effect of tranexamic acid on transfusion rate in 
primary total hip arthroplasty. J Arthroplasty. 2014 Feb;29(2):387-9. PubMed PMID: 
23790499.   
12. Vigna-Taglianti F, Basso L, Rolfo P, Brambilla R, Vaccari F, Lanci G, Russo R. 
Tranexamic acid for reducing blood transfusions in arthroplasty interventions: a 
costeffective practice. Eur J Orthop Surg Traumatol. 2014 May;24(4):545-51. PubMed 
PMID: 23633085.   
13. Kelley TC, Tucker KK, Adams MJ, Dalury DF. Use of tranexamic acid results in 
decreased blood loss and decreased transfusions in patients undergoing staged 
bilateral total knee arthroplasty. Transfusion. 2014 Jan;54(1):26-30. PubMed PMID: 
23521109.   
14. Imai N, Dohmae Y, Suda K, Miyasaka D, Ito T, Endo N. Tranexamic acid for reduction 
of blood loss during total hip arthroplasty. J Arthroplasty. 2012 Dec;27(10):1838-43. 
PubMed PMID: 22704229.   
15. Charoencholvanich K, Siriwattanasakul P. Tranexamic acid reduces blood loss and 
blood transfusion after TKA: a prospective randomized controlled trial. Clin Orthop 
Relat Res. 2011 Oct;469(10):2874-80. PubMed PMID: 21512813; PubMed Central 
PMCID: PMC3171556.   
16. Huang Z, Ma J, Shen B, Pei F. Combination of Intravenous and Topical Application of 
Tranexamic Acid in Primary Total Knee Arthroplasty: A Prospective Randomized 
Controlled Trial. J Arthroplasty. 2014 Jun 5;PubMed PMID: 25007725.   
17. Tuttle JR, Ritterman SA, Cassidy DB, Anazonwu WA, Froehlich JA, Rubin LE. Cost 
benefit analysis of topical tranexamic acid in primary total hip and knee arthroplasty. 
J Arthroplasty. 2014 Aug;29(8):1512-5. PubMed PMID: 24630599.  
18. Karam JA, Bloomfield MR, DiIorio TM, Irizarry AM, Sharkey PF. Evaluation of the 
efficacy and safety of tranexamic acid for reducing blood loss in bilateral total knee 
arthroplasty. J Arthroplasty. 2014 Mar;29(3):501-3. PubMed PMID: 24051240.   
19. Chimento GF, Huff T, Ochsner JL Jr, Meyer M, Brandner L, Babin S. An evaluation of 
the use of topical tranexamic acid in total knee arthroplasty. J Arthroplasty. 2013 
Sep;28(8 Suppl):74-7. PubMed PMID: 24034510.   
20. Whiting DR, Gillette BP, Duncan C, Smith H, Pagnano MW, Sierra RJ. Preliminary 
results suggest tranexamic acid is safe and effective in arthroplasty patients with 
severe comorbidities. Clin Orthop Relat Res. 2014 Jan;472(1):66-72. PubMed PMID: 
23817754; PubMed Central PMCID: PMC3889421.   
21. Sabbag, O.D., et al., Tranexamic Acid Was Safe in Arthroplasty Patients With a History 
of Venous Thromboembolism: A Matched Outcome Study. J Arthroplasty, 2017. 
32(9S): p. S246-S250.  
22. Whiting, D.R., et al., Preliminary results suggest tranexamic acid is safe and effective 
in arthroplasty patients with severe comorbidities. Clin Orthop Relat Res, 2014. 
472(1): p. 66-72.  
23. Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults. 
Surgery. 1962;51:224–32. PubMed PMID: 21936146  
24. Good L, Peterson E, Lisander B. Tranexamic acid decreases external blood loss but not 
hidden blood loss in total knee replacement. Br J Anaesth. 2003;90:596–9. PubMed 
PMID: 12697586  

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25. Lisander B, Ivarsson I, Jacobsson SA. Intraoperative autotransfusion is associated 
with modest reduction of allogeneic transfusion in prosthetic hip surgery. Acta 
Anaesthesiol Scand. 1998;42:707–12. PubMed PMID: 9689278  
26. Foss NB, Kehlet H. Hidden blood loss after surgery for hip fracture. J Bone Joint Surg 
Br. 2006;88:1053–9. PubMed PMID: 16877605  
  
C. Rationale  
The large bony and soft tissue tumor resections performed in musculoskeletal oncologic 
patients presents the potential for significant blood loss.  With basic arthroplasty being 
associated with significant intraoperative and postoperative blood loss often necessitating 
blood transfusion1, larger bony resections with the use of endoprostheses presents an 
even higher risk2.  Transfusions themselves are not without known complications. 
Examples include infection, hemolytic transfusion reaction, and increased short-term 
mortality1,3. Tranexamic acid (TXA), a synthetic analog of lysine, is an antifibrinolytic that 
is used to reduce blood loss. TXA works by blocking the lysine binding sites on 
plasminogen4. Perioperative use of TXA has been shown to decrease intraoperative and 
postoperative blood loss and decrease transfusion rates in both total knee arthroplasty 
and total hip arthroplasty5-15. It has also been shown to result in higher postoperative 
hemoglobin13. TXA also has been shown to decrease postoperative pain, swelling, length 
of hospital stay, and result in higher patient satisfaction16.  
  
This project has the potential to make a profound impact on how musculoskeletal 
oncology patients undergoing endoprosthetic reconstruction are managed in the 
perioperative period.  This project will advance our knowledge in the musculoskeletal 
oncology field by potentially showing a significant correlation between administration of 
TXA and decreased rates of blood transfusions and perioperative blood loss.  This has 
already been shown in the total joint arthroplasty literature.  However, there is a lack of 
available literature that shows the effects of TXA on the patient population we wish to 
study.  Because of this the use of TXA in this patient population is sporadic and varies 
widely from surgeon to surgeon.  Providing a definitive answer regarding the safety and 
efficacy of TXA in this patient population would both unify the musculoskeletal oncology 
field in their use or abandonment of TXA, and potentially improve oncologic patient care 
in a similar fashion than that seen with the use of TXA in arthroplasty.  The clinical 
outcomes that are evaluated by this project have the potential to make a profound 
impact on the lives of the patients we care for on a day-to-day basis.    
  
This project has the potential to improve clinical outcomes of musculoskeletal oncology 
patients undergoing endoprosthetic reconstruction with TXA.  Examples of potential 
improved clinical outcomes that could be derived from this project are: decreased 
intraoperative and postoperative blood loss and decreased transfusion rates with 
administration of TXA in this specific patient population.  
  
II.  
Research Plan and Design  
  
A. Study Objectives: Specific Aims: to determine if there is any significant difference in 
perioperative blood loss and blood transfusion rates when TXA is used compared to when it 

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is not used in patients undergoing radical resection of bone and soft tissue sarcomas with 
endoprosthetic reconstruction.  Statement of Purpose: to determine in a randomized 
controlled fashion if there is any difference in perioperative blood loss and blood transfusion 
rates following radial resection of malignant bony tumors with endoprosthetic reconstruction 
when TXA is used compared to when it is not.  Primary outcome measure:  determination of 
perioperative blood loss. To do this, values will be recorded preoperatively and compared to 
post-operative values. Perioperative blood loss will be calculated using the Hemoglobin 
balance method.23-26 Secondary outcome measures: (1) Blood transfusion rates.  (2) 
Surgical drain output.    
B. Study Type and Design: Type of Study: multi-center prospective randomized controlled 
trial.  Study Design: We will initially monitor 4 groups of patients.  The first group (20 
patients) will undergo bony tumor resection of the femur or proximal tibia and  
endoprosthetic reconstruction with TXA. The second group (20 patients) will undergo bony 
tumor resection of the femur or proximal tibia and endoprosthetic reconstruction without 
TXA. The third group (50 patients) will undergo soft tissue sarcoma resection of the lower 
extremity with TXA.  The fourth group (50 patients) will undergo soft tissue sarcoma 
resection of the lower extremity without TXA. The use of TXA is well established for 
arthroplasty at this institution given the body of evidence supporting both efficacy and 
safety.  Treatment assignments will be stratified by type of resection location. Patient 
randomization will be done via randomization program through REDCap.  The randomization 
process will be performed centrally at Kansas University Medical Center and the treating 
surgeon will not have access to the randomization list.  Randomization will occur prior to 
definitive surgical procedure, and the treating surgeon and pharmacy will be notified to 
ensure adequate vials of tranexamic acid are available in the operating room  
(investigators/surgeons are not blinded).  Patients will be blinded to treatment allocation.  
Those in groups using TXA will receive 1g TXA IVPB 10 minutes prior to incision and a 
second dose of 1g IVPB at the time of closure which is the standard protocol used for total 
joint arthroplasty.  The TXA will be administered by the anesthesia team. If the surgeon 
determines intraoperatively that TXA is required for patient safety, the drug should be used.   
Patients receiving a non-standard dosing of TXA will then be excluded from the study.  
Routine hemoglobin and hematocrit measurements will be observed preoperatively as well as 
postoperatively at 6 hours and in the mornings of postoperative days 1-3.  This laboratory 
regimen is currently the standard of care and utilized routinely.  Patients may be discharged 
prior to obtaining all 4 blood draws.  If a patient is discharged prior to postoperative day 3, 
no additional blood draw will be performed.  Additionally, both intraoperative and 
postoperative incidents of blood transfusion will be monitored to calculate transfusion rates.  
Postoperative erythrocyte transfusions will be given for hemoglobin below 7.0 as is the 
current practice guidelines used by the attending surgeons at this institution.  Other facilities 
are encouraged to follow this protocol, however, the ultimate decision for blood transfusion 
will be at the discretion of the treating physician.  Surgical drains are also used routinely and 
their daily output will be recorded until they are deemed appropriate to pull by the attending 
surgeon.  Patients will be clinically monitored daily while in the hospital and in subsequent 
follow up visits for symptoms of DVT or embolism and appropriate diagnostic screening with 
venous Doppler will be utilized if symptoms are present, as is also part of current routine 
postoperative care. Our DVT prophylaxis protocol postoperatively will be 4 weeks of aspirin 
81 mg BID unless medical co-morbitities necessicate the use of other anti-coagulation.  
Mechanical DVT prophylaxis in the form of sequential compression devices will also be 

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utilized.  We also plan to record patient specific factors including age, sex, smoking status, 
BMI, pre-op diagnosis, operative time, comorbidities, and length of stay.  These variables will 
be analyzed independently to detect any correlation with perioperative blood loss and 
erythrocyte transfusion rate.  
  
C. Sample size, statistical methods, and power calculation  
Method of Randomization: Patient randomization will be done via a randomization 
program through REDCap.  The randomization process will be performed centrally at 
Kansas University Medical Center and the treating surgeon will not have access to the 
randomization list. Randomization will occur prior to definitive surgical procedure, and the 
treating surgeon and pharmacy will be notified to ensure adequate vials of tranexamic 
acid are available in the operating room (investigators/surgeons are not blinded). 
Patients will be blinded to treatment allocation. Treatment assignments will be stratified 
by type of resection.  A power of 0.9 would require a total of 40 patients (20 per 
treatment group) be enrolled in the bony tumor group and 100 patients (50 per 
treatment group) in the soft tissue tumor group.   
  
Since we are gathering entirely objective data the treating surgeon does not need to be 
blinded.  Group differences in preoperative hemoglobin and hematocrit, transfusion 
requirements, drain output at 24 hours, and changes in hemoglobin and hematocrit will 
be compared using pairwise Student T-test analysis.  Pairwise T-tests between each of 
the groups (for continuous variables) and Chi squared analysis (for categorical variables) 
will be used to determine if a statistically significant difference exists between the groups 
in terms of the patient specific factors that are also collected and analyzed (age, sex, 
smoking status, BMI, operative time, length of stay).  
  
D. Subject Criteria (See Vulnerable Populations appendix, if applicable):   
Inclusion criteria: Patients (male or female) between the ages of 18-90 undergoing wide 
resection of a malignant bony tumor of the lower extremity with endoprosthetic 
reconstruction or resection of soft tissue sarcoma measuring >5cm.  
  
Exclusion criteria:   
• 
Patients undergoing revision endoprosthetic reconstruction  
• 
Patients with known coagulopathy   
• 
Known history of DVT or embolic disease   
• 
Benign tumors   
• 
Patients with allergy to TXA  
• 
Those refusing blood products   
• 
Those concurrently on anti-coagulant therapy   
• 
Pregnant and nursing women   
• 
Vulnerable populations as defined by the University of Kansas Medical Center IRB  
  
Withdrawal/Termination criteria: The subject’s participation will be terminated by the 
investigator if the subject wishes to withdrawal from the study at any point in time.  In 
the event that a disproportionate number of complications are occurring in one of the 
study groups, the study will be suspended and the IRB will be consulted.  There are no 

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safety precautions that need to be applied to subjects who withdraw from the study.  The 
withdrawn patients will be routinely followed on an outpatient basis in a clinic setting.    
  
  
E.  Specific methods and techniques used throughout the study   
  
1. Laboratory tests: Complete Blood Count (CBC) – the purpose of collection is to help 
determine the effect of TXA on hemoglobin and hematocrit levels.  A CBC would be 
collected pre-operatively and post-operatively at 6 hours and in the mornings of 
postoperative days 1, 2, and 3.  Patients may be discharged prior to obtaining all 4 blood 
draws.  If a patient is discharged prior to postoperative day 3, no additional blood draw 
will be performed. Blood specimens will need to be collected for this test.  This test is 
routinely ordered in the hospital setting and is the standard of care for evaluating and 
monitoring blood loss post-operatively.  
2. Study Procedures: Describe each procedure to be used in the study, including the 
instruments used, time required for each procedure, cognitive assessments, etc. The 
patient’s consented for this study and randomized to the TXA group will receive TXA 
while in the operating room as part of the routine administration of anesthesia.  This is 
not technically considered a procedure.  
3. Clearly indicate which procedures, tests, visits, etc., are parts of usual standard therapy 
and which are performed solely for research purposes. Make it clear which tests are 
routinely performed for clinical care but are providing data for the research (and are 
billable to insurance companies), and which tests are only performed for research 
purposes (not billable to insurance companies). Usual standard therapy: all postoperative 
clinic visits, pre-operative and post-operative CBC.   These CBCs would be providing data 
for this clinical trial. No tests will be ordered that are only performed for research 
purposes.  
4. Describe the fate of any body component:  No body components will be obtained during 
this study.  
5. Timeline: Patients will be seen at routine post-operative visits at 2-3 weeks, 6 weeks, 
and 3 months where clinical examination and history taking will take place.  
  
F. 
Risk/benefit assessment:   
1. Physical risk: The primary concern with the use of TXA is the theoretical risk of 
developing a deep venous thrombosis.  The patients will be monitored clinically for signs 
and symptoms of DVT while they are admitted to the hospital as well as at routine 
postoperative visits.   
2. Psychological risk: We do not anticipate any psychologic risk to participants in this study.   
3. Social risk: We do not anticipate any social risk in this study.   
4. Economic risk: There will be no cost to subjects during this study, neither will there by 
any remuneration.  
5. Potential benefit of participating in the study   
a. to the individual subject and/or parent if any: None  
b. to the population from which the subject is drawn: TXA in this patient population 
is sporadic and varies widely from surgeon to surgeon.  Providing a definitive 
answer regarding the safety and efficacy of TXA in this patient population would 
both unify the musculoskeletal oncology field in their use or abandonment of TXA, 

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and potentially improve oncologic patient care in a similar fashion than that seen 
with the use of TXA in arthroplasty.  
c. to science, society, and humanity in general: A definitive answer regarding the 
safety and efficacy of TXA in this patient population would both unify the 
musculoskeletal oncology field in their use or abandonment of TXA  
G. 
Location where study will be performed: This will be a multi-institutional study with 
the University of Kansas Medical Center being the coordinating site. We have interest from 
multiple institutions but they are awaiting our IRB approval.  These include the University of 
Chicago, Oklahoma, St. Louis University, Cleveland Clinic, and MUSC, Iowa, Penn, and others.  
Recruitment of study participants will take place at the University of Kansas Medical Center and 
the University of Kansas Hospital Indian Creek Campus.  Recruitment will also take place at 
participating institutions.  Data will be collected for the primary and secondary endpoints from 
patients’ electronic medical records and will be compiled electronically.  The research subject’s 
records will be stored electronically on a hard-drive in a passwordprotected and encrypted 
computer at the University of Kansas Medical Center H. Collaboration (with another 
institution, if applicable): see Item “I” below.  
I. Single IRB Review for a Multi-site study (if applicable):    
1. For which sites will KUMC serve as the IRB of record? Only Kanas University Medical 
Center.  Participating institutions will work through their own IRBs for review and 
approval.   
2. Indicate which study activities will occur at each site. If all study procedures will be 
identical across study sites, state this.  Identical across sites.  
3. Describe how you will assess the capacity of each site to perform the research (e.g., 
expertise, staffing, space, equipment, etc.)  If applicable, include site evaluation tools in 
your IRB submission.  All sites will have a fellowship trained orthopaedic oncologist who 
treats sarcomas regularly.  They will all be at academic institutions with their own IRBs 
and experience in conducting clinical trials.  
4. Describe how the lead investigators will ensure that all participating sites use the 
IRBapproved version of the protocol, consent, recruitment materials and other study 
documents. We will have mobile monthly phone conferences to discuss enrollment and 
issues related to the study. Further contact will be provided by Sharon Bradshaw, the 
orthopaedic department’s research coordinator. Approved protocol documents will be sent 
by study coordinator/PI directly to participating sites’ designated research team 
members.  Any updated documents will be sent to all sites as soon as they are approved. 
Describe how the lead investigators will communicate with and disseminate new 
information to other sites (e.g., training meetings, regularly-scheduled conference calls, 
notifications, etc.) We will have mobile monthly phone conferences to discuss enrollment 
and issues related to the study.  Sites not included on those conferences will be 
contacted directly by the PI (Kyle Sweeney) or study coordinator (Sharon Bradshaw).  
5. Describe how the lead investigator will assess protocol compliance, unanticipated 
problems and adverse events at other sites. We will have mobile monthly phone 
conferences to discuss enrollment and issues related to the study. In addition, Sharon 
Bradshaw will be available to be contacted by other institution to answer questions 
regarding the protocol.  I will be in contact with the other PIs at the monthly meeting.  
6. Name the member of the KUMC study team who will be the point of contact to coordinate 
oversight and communication with the sites.  Sharon Bradshaw   

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J. Community-Based Participatory Research (if applicable) 1. 
Participants and the nature of their involvement: N/A  
  
2. Cultural issues: We do not anticipate cultural or community attitudes to affect the 
research study.  A certified interpreter will be utilized during the recruitment and consent 
process if needed.  
  
3. Origin of the research question: The impetus and idea for this study came from the 
researchers alone.  
  
4. Risks and Benefits: N/A  
  
5. Study Description and Process: N/A  
  
6. Return of results: The results will be published by the principle investigator and 
coinvestigators.  There is not an explicit agreement between researchers and community 
participants about the research results.    
  
7. Sustainability: N/A  
  
K. Personnel who will conduct the study, including:  
1. Indicate, by title, who will be present during study procedure(s): Dr. Kyle Sweeney MD,  
Dr. Howard Rosenthal MD, Dr. Jacob Birlingmair MD   
2. Primary responsibility for the following activities, for example:   
a. Determining eligibility: Dr. Kyle Sweeney MD, Dr. Howard Rosenthal MD, Dr.  
Kimbery Templeton, MD  
b. Obtaining informed consent: Dr. Kyle Sweeney MD, Dr. Howard Rosenthal MD, Dr.  
Kimberly Templeton MD   
c. Providing on-going information to the study sponsor and the IRB: Dr. Kyle  
Sweeney MD, Dr. Jacob Birlingmair MD, Sharon Bradshaw   
d. Maintaining participant's research records: Dr. Kyle Sweeney MD, Dr. Jacob  
Birlingmair MD, Sharon Bradshaw   
e. Completing physical examination: Dr. Kyle Sweeney MD, Dr. Howard Rosenthal  
MD, Dr. Kimberly Templeton MD  
f. 
Taking vital signs, height, weight: Clinical support staff for participating surgeons  
g. Drawing / collecting laboratory specimens: Clinical support staff for participating 
surgeons  
h. Performing / conducting tests, procedures, interventions, questionnaires: Dr. Kyle  
Sweeney MD, Dr. Howard Rosenthal MD, Dr. Kimberly Templeton MD  

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i. 
Completing study data forms: Dr. Kyle Sweeney MD, Dr. Jacob Birlingmair MD,  
Dr. Howard Rosenthal MD,  Dr. Kimberly Templeton MD  
j. 
Managing study database: Dr. Kyle Sweeney MD, Dr. Jacob Birlingmair MD, Sharon 
Bradshaw   
  

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L. Assessment of Subject Safety and Development of a Data and Safety Monitoring Plan  
  
1. Please note that any study proposal with more than minimal risk must include a data and 
safety monitoring plan.  Elements of the plan include:  
a. Persons/groups who will review the data (study team; independent safety 
monitor, data monitoring committee or formal DSMB) - Study team  
i. An independent safety monitor will be used.  Dr. Brent Wise, MD is 
an orthopaedic surgeon familiar with the use of TXA and uninvolved 
with the study in any other capacity.  
   
b. Data/events that will be reviewed - Adverse events/complications arising in the 
participating patients.  
c. Frequency of review: Review will occur every 4 months routinely.  Additionally, a 
review will be conducted if 5 separate adverse events are reported prior to the 
scheduled bi-annual review.   
d. Types of analyses to be performed – we will analyze the rate of complications 
(infections, PE, DVT) between the groups to make sure that we aren’t getting 
statistically significant differences between groups  
e. Safety-related triggers that would cause the PI to stop or alter the study – If our 
analysis of complications reveals a statistically significant difference between 
groups, we will place the study on hold until an appropriate remedy can be 
reached.  We will consult with the IRB before resuming the study.  If no remedy 
can be determined the study will be permanently held  
2. Describe how adverse events and unanticipated problems will be ascertained and 
handled.  Explain exactly which type of problems will be considered serious and reported 
to the IRB. The reporting timeframe should also be detailed - Sites will report serious 
adverse events and unanticipated problems within 72 hours to coordinating center 
(KUMC). The independent monitor and Primary investigator will be made aware and the 
independent safety monitor will determine if a further review is necessary and/or further 
action needs to be taken.  
3. Explain exactly what will happen if a patient experiences an adverse event or other 
problem (for example, will discontinue study participation) - Serious adverse events will be 
reviewed by the independent safety monitor, principal investigator, and treating surgeon where it 
will be determined if study participation should be continued or not.  
  
  
III.  
Subject Participation  
  
A. Recruitment:  
Patients that present to participating surgeons’ clinics that meet inclusion criteria and do 
not meet exclusion criteria will be recruited for this study. The treating surgeon will 
conduct all of the recruitment and consent aspects of this study in his or her clinic.  If the 
treating surgeon deems a patient to be eligible for this study based on our inclusion and 
exclusion criteria then these patients will be asked to participate in this study in a 

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noncoercive manner.  We will not construct any advertisements or flyers that attempt to 
recruit study subjects.  
Attach a copy of the recruitment letter or introductory statement and describe planned 
use or distribution of the document. We will not use a recruitment letter for this study.   
B. Screening Interview/questionnaire: N/A.  We will not use interviews or questionnaires 
for screening.  In order to be included in this study the subjects must meet set parameters 
(inclusion and exclusion criteria).  Evaluation of whether patients can be included in this 
study will be based on chart review and patient history acquisition.  This will be performed by 
participating surgeon.  
C. Informed consent process and timing of obtaining of consent  
1 
Indicate who will give subjects detailed and comprehensive information about the study 
and obtain their written consent. The treating surgeon or designated coordinator will give 
subjects detailed and comprehensive information about the study and will obtain their 
written consent.  The same standard principals that guide obtaining informed consent for 
their surgical procedure will be used.    
2 
Indicate how the consenting process will be structured to ensure independent and 
thoughtful decision-making, and what steps will be taken to avoid coercion and 
guarantee confidentiality. The same standard principals that guide obtaining informed 
consent for a surgical procedure will be used.  
3 
Indicate how, and by whom, it will be determined whether the subject is able to give 
informed consent, or whether their legal guardian will give informed consent. For 
subjects whose ability to give informed consent may be compromised by cognitive and/or 
decisional impairment (examples may include individuals with a psychiatric disorder, an 
organic impairment, a developmental disorder, or those suffering from a terminal illness, 
degenerative disease, severe physical handicap or dependence on drugs or alcohol), 
complete Appendix I. The same standard principals that guide obtaining informed 
consent for surgical procedures will be used.  Patients unable to give informed consent 
will not be included in the study.  
D. Alternatives to Participation: Statement of Alternatives: The only alternative to 
participating in this study is not to participate.  All subjects have the right to withdraw from 
the study at any time.  If you wish to be removed from this study, you can contact Dr. Kyle 
Sweeney.  
E. Costs to Subjects: The laboratory tests/follow up visits that will occur during this study are 
standard as defined by the principle investigator regardless of whether the patient 
participates in the study. For example, a patient who chose to not participate in this study 
will undergo the same tests/labs/follow up appointments as a patient who decided to 
participate in this study.  We do not anticipate any costs will be related solely to subjects 
participating in this study.    
F. How new information will be conveyed to the study subject and how it will be 
documented: New information will be given to study subjects in writing.  
G. Payment, including a prorated plan for payment: Subjects will not be paid or 
reimbursed for their participation in this study.  

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H. Payment for a research-related injury: If injury or illness is a direct result of 
participation in this study, immediate treatment will be provided as deemed appropriate by 
the principle investigator.  However, the cost of that treatment will be billed to the individual  
or their insurance company.  The patient will be aware that their insurance company may 
decide not to pay.  
IV.  
Data Collection and Protection  
 
1.  
Data Management and Security:   
The principle investigator and co-investigators will have sole access to the study data.  
All data will be stored in the KUMC department network drive provided by Information  
Resources.  An encrypted file location will be requested by contacting KUMC Information 
Security.  Human subjects will be identifiable via their medical record number.  No linking 
list will be maintained following data collection and final submission to an academic 
journal which will protect the identity and confidentiality of patients.  Data will be stored 
on a password protected computer within the KUMC department drive and only 
utilized/viewed by the principle investigator and co-investigators. Data analysis conducted 
on a private computer will occur only using data that is void of personal identifiable 
information.  Data will not be shared with individuals outside of KUMC.  The individual 
accessing the data would like to preserve the data for a sufficient time to complete the 
collection, analysis, and final submission to an academic journal.   It is anticipated that 
the list that links the subject’s identity to the study data will be destroyed within 3 years 
of study completion.  
  
A. Sample / Specimen Collection: N/A  
B. Tissue Banking Considerations: N/A  
C. Procedures to protect subject confidentiality: The risk of loss of confidentiality will be 
minimized by the fact that the data will be managed by the study investigators (who will 
have sole access to the data), and stored electronically on a hard-drive in a 
passwordprotected and encrypted computer at the University of Kansas Medical Center.  The 
records will be kept using each patient’s medical record number, age, and sex.  No other 
identifiers will be used in this study.  
D. Quality Assurance / Monitoring  
1.  
Describe steps to be taken to assure that the data collected are accurate, consistent, 
complete and reliable. (source data verification, audits or self – assessment) Source 
data verification and self-audits will be performed.  The protocol for the clinical trial 
will be spelled out for the participants.  A discussion will be had between the PI at  
KUMC and the PI at the participating institution to ensure the protocol is understood.  
  
V.  
Data Analysis and Reporting  
A. Statistical and Data Analysis: Group differences in preoperative hemoglobin and 
hematocrit, transfusion requirements, drain output at 24 hours, difference in hemoglobin 
balance method, and changes in hemoglobin and hematocrit will be compared using pairwise 
Student T-test analysis.  Pairwise T-tests between each of the groups (for continuous 

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variables) and Chi squared analysis (for categorical variables) will be used to determine if a 
statistically significant difference exists between the groups in terms of the patient specific 
factors that are also collected and analyzed (age, sex, smoking status, BMI, operative time, 
length of stay, presence of coagulopathy, specific anticoagulation regimen should it differ  
from study protocol, size of resection, depth of resection, location of tumor, pathologic 
diagnosis, stage of disease).  
B. Outcome: We expect the results to be similar to the TXA arthroplasty studies/literature with 
regards to decreased perioperative blood loss and decreased transfusion rates. There are not 
necessarily any criteria for success or failure.  The results of this study will help provide a 
definitive answer regarding the safety and efficacy of TXA in oncologic patients.  This will 
help unify the musculoskeletal oncology field in their use or abandonment of TXA.  
C. Study results to participants: The study results/conclusions will not be given to subjects 
unless they are specifically asked for at future scheduled outpatient clinic visits.  Once the 
proposed study is completed a conversation with subjects can occur on an outpatient basis 
at their routine scheduled clinic visits regarding our results and conclusions if desired.  The 
subjects reserve the right to know what conclusions were drawn from the study they directly 
participated in.  In addition, we plan to publish a manuscript with our results/conclusions 
after completion of the study which can be sought after if desired.   
D. Publication Plan: The results will be published by the principal investigator and 
coinvestigators within the orthopaedic surgery department.  Results will be submitted for 
publishing within 6 months of data analysis. The principal investigator and co-investigators 
within the department of orthopaedic surgery will be primarily involved in the compilation of 
the study results.  
VI.  
Bibliography / References / Literature Cited   
  
References:  
1. Sabatini L, Atzori F, Revello S, Scotti L, Debiasi F, Massè A. Intravenous use of tranexamic acid 
reduces postoperative blood loss in total knee arthroplasty. Arch Orthop Trauma Surg. 2014 Sep 
3;PubMed PMID: 25179896.   
2. Borisov DB, Iudin SV, Tiuriapin AA, Kapinos AA, Vyl'iurov IV, Kazakevich EV. [Prevention and 
treatment of anemia during endoprosthetic replacement of large joints]. Anesteziol Reanimatol. 
2010 Mar-Apr;PubMed PMID: 20524332.   
3. Wei W, Wei B. Comparison of Topical and Intravenous Tranexamic Acid on Blood Loss and 
Transfusion Rates in Total Hip Arthroplasty. J Arthroplasty. 2014 Jul 30;PubMed PMID: 
25155138.   
4. Aguilera X, Martinez-Zapata MJ, Bosch A, Urrútia G, González JC, Jordan M, Gich I, Maymó RM, 
Martínez N, Monllau JC, Celaya F, Fernández JA. Efficacy and safety of fibrin glue and tranexamic 
acid to prevent postoperative blood loss in total knee arthroplasty: a randomized controlled 
clinical trial. J Bone Joint Surg Am. 2013 Nov 20;95(22):2001-7. PubMed PMID: 24257657.   
5. Bidolegui F, Arce G, Lugones A, Pereira S, Vindver G. Tranexamic Acid Reduces Blood Loss and 
Transfusion in Patients Undergoing Total Knee Arthroplasty without Tourniquet: A Prospective 
Randomized Controlled Trial. Open Orthop J. 2014;8:250-4. PubMed PMID: 25132872; PubMed 
Central PMCID: PMC4133924.   

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6. Samujh C, Falls TD, Wessel R, Smith L, Malkani AL. Decreased blood transfusion following 
revision total knee arthroplasty using tranexamic Acid. J Arthroplasty. 2014 Sep;29(9 
Suppl):182-5. PubMed PMID: 25015759.   
7. Levine BR, Haughom BD, Belkin MN, Goldstein ZH. Weighted versus uniform dose of tranexamic 
Acid in patients undergoing primary, elective knee arthroplasty: a prospective randomized 
controlled trial. J Arthroplasty. 2014 Sep;29(9 Suppl):186-8. PubMed PMID: 24997651.   
8. Soni A, Saini R, Gulati A, Paul R, Bhatty S, Rajoli SR. Comparison between intravenous and 
intra-articular regimens of tranexamic acid in reducing blood loss during total knee arthroplasty. 
J Arthroplasty. 2014 Aug;29(8):1525-7. PubMed PMID: 24814890.   
9. Yue C, Kang P, Yang P, Xie J, Pei F. Topical Application of Tranexamic Acid in Primary Total Hip 
Arthroplasty: A Randomized Double-Blind Controlled Trial. J Arthroplasty. 2014 Mar 29;PubMed 
PMID: 24793893.  
10. Chang CH, Chang Y, Chen DW, Ueng SW, Lee MS. Topical tranexamic acid reduces blood loss and 
transfusion rates associated with primary total hip arthroplasty. Clin Orthop Relat Res. 2014 
May;472(5):1552-7. PubMed PMID: 24385043; PubMed Central PMCID: PMC3971210.    
11. Wind TC, Barfield WR, Moskal JT. The effect of tranexamic acid on transfusion rate in primary 
total hip arthroplasty. J Arthroplasty. 2014 Feb;29(2):387-9. PubMed PMID: 23790499.   
12. Vigna-Taglianti F, Basso L, Rolfo P, Brambilla R, Vaccari F, Lanci G, Russo R. Tranexamic acid for 
reducing blood transfusions in arthroplasty interventions: a cost-effective practice. Eur J Orthop 
Surg Traumatol. 2014 May;24(4):545-51. PubMed PMID: 23633085.   
13. Kelley TC, Tucker KK, Adams MJ, Dalury DF. Use of tranexamic acid results in decreased blood 
loss and decreased transfusions in patients undergoing staged bilateral total knee arthroplasty. 
Transfusion. 2014 Jan;54(1):26-30. PubMed PMID: 23521109.   
14. Imai N, Dohmae Y, Suda K, Miyasaka D, Ito T, Endo N. Tranexamic acid for reduction of blood 
loss during total hip arthroplasty. J Arthroplasty. 2012 Dec;27(10):1838-43. PubMed PMID: 
22704229.   
15. Charoencholvanich K, Siriwattanasakul P. Tranexamic acid reduces blood loss and blood 
transfusion after TKA: a prospective randomized controlled trial. Clin Orthop Relat Res. 2011 
Oct;469(10):2874-80. PubMed PMID: 21512813; PubMed Central PMCID: PMC3171556.   
16. Huang Z, Ma J, Shen B, Pei F. Combination of Intravenous and Topical Application of Tranexamic 
Acid in Primary Total Knee Arthroplasty: A Prospective Randomized Controlled Trial. J 
Arthroplasty. 2014 Jun 5;PubMed PMID: 25007725.   
17. Tuttle JR, Ritterman SA, Cassidy DB, Anazonwu WA, Froehlich JA, Rubin LE. Cost benefit analysis 
of topical tranexamic acid in primary total hip and knee arthroplasty. J Arthroplasty. 2014 
Aug;29(8):1512-5. PubMed PMID: 24630599.   
18. Karam JA, Bloomfield MR, DiIorio TM, Irizarry AM, Sharkey PF. Evaluation of the efficacy and 
safety of tranexamic acid for reducing blood loss in bilateral total knee arthroplasty. J 
Arthroplasty. 2014 Mar;29(3):501-3. PubMed PMID: 24051240.   
19. Chimento GF, Huff T, Ochsner JL Jr, Meyer M, Brandner L, Babin S. An evaluation of the use of 
topical tranexamic acid in total knee arthroplasty. J Arthroplasty. 2013 Sep;28(8 Suppl):74-7. 
PubMed PMID: 24034510.   
20. Whiting DR, Gillette BP, Duncan C, Smith H, Pagnano MW, Sierra RJ. Preliminary results suggest 
tranexamic acid is safe and effective in arthroplasty patients with severe comorbidities. Clin 
Orthop Relat Res. 2014 Jan;472(1):66-72. PubMed PMID: 23817754; PubMed Central PMCID: 
PMC3889421.   
21. Sabbag, O.D., et al., Tranexamic Acid Was Safe in Arthroplasty Patients With a History of 
Venous Thromboembolism: A Matched Outcome Study. J Arthroplasty, 2017. 32(9S): p. 
S246S250.  

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22. Whiting, D.R., et al., Preliminary results suggest tranexamic acid is safe and effective in 
arthroplasty patients with severe comorbidities. Clin Orthop Relat Res, 2014. 472(1): p. 66-72.  
23. Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults. Surgery. 
1962;51:224–32. PubMed PMID: 21936146  
24. Good L, Peterson E, Lisander B. Tranexamic acid decreases external blood loss but not hidden 
blood loss in total knee replacement. Br J Anaesth. 2003;90:596–9. PubMed PMID: 12697586  
25. Lisander B, Ivarsson I, Jacobsson SA. Intraoperative autotransfusion is associated with modest 
reduction of allogeneic transfusion in prosthetic hip surgery. Acta Anaesthesiol Scand. 
1998;42:707–12. PubMed PMID: 9689278  
26. Foss NB, Kehlet H. Hidden blood loss after surgery for hip fracture. J Bone Joint Surg  
Br. 2006;88:1053–9. PubMed PMID: 16877605  
  
APPENDIX I: VULNERABLE POPULATIONS  
  
I. 
The recruitment plan will not include any of the groups noted below.  
  
II. 
Cognitively or decisionally impaired individuals: N/A.  Cognitively or decisionally impaired 
individuals will be excluded from this study.  
  
III. 
Children: N/A.  Children will be excluded from this study.  
  
IV. 
Pregnant women: N/A.  Pregnant women will be excluded from this study.  
  
V. 
Prisoners: N/A.  Prisoners will be excluded from this study.  
  
VI. 
Students and/or Employees: N/A.  Students and/or Employees at KUMC will be excluded 
from this study.