Tranexamic Acid (TXA) to Reduce Volume Of Blood Transfused In Pediatric And Young Adult Cancer Patients Undergoing Limb Salvage Procedure Of A Lower Extremity
Phase: PHASE3
Conditions: Cancer of the Bone, Limb Salvage
Sponsor: St. Jude Children's Research Hospital

Revision 5.1 dated 03-21-2023
Protocol document date: 03-21-2023
St. Jude 
TXAKIDS-NCT04410042
Initial version, dated: 03-22-19 (IRB approved: 02-03-20) Activated: 
Amendment 1.0, dated 02-17-20 (IRB approved: 04-16-20) Activated:
Amendment 2.0, dated: 04-22-20 (IRB approved: 06-04-20) Activated: 
Amendment 3.0, dated 08-20-20 (IRB approved: XX-XX-XX) Activated: 
Amendment 3.1, dated 01-25-2021 (IRB approved: XX-XX-XX) Activated: 
Amendment 4.0, dated 04-28-2021 (IRB approved: XX-XX-XX) Activated: 
Amendment 5.0, dated 01-06-2023 (IRB approved: XX-XX-XX) Activated:
Revision 5.1, dated 03-21-2023 (IRB approved: XX-XX-XX) Activated:
TRANEXAMIC ACID (TXA) TO REDUCE VOLUME OF BLOOD TRANSFUSED IN 
PEDIATRIC AND YOUNG ADULT CANCER PATIENTS UNDERGOING LIMB 
SALVAGE PROCEDURE OF A LOWER EXTREMITY
IND 147543
Faculty Sponsor
Andrew Davidoff, MD1
Principal Investigator
Michael D. Neel, MD1
Co-Investigators 
Andrew M. Davidoff, MD1
Michael W. Bishop, MD2
Michael Frett, MD3
Julie Richardson, PharmD4
Sandra W. Murphy, FNP1
Michael G. Rossi, MD5
Haitao Pan, PhD6
Xiaomeng Yuan, PhD6
Ulrike Reiss, MD5
Brian DeFeo, PT7
Kirsten Ness, PhD8
Abdelhafeez Abdelhafeez, MD1
Lindsay Talbot, MD1
1Department of Surgery 
2Department of Oncology 
3Department of Hematology
4Department of Pharmaceutical Services 
5Division of Anesthesiology 
6Department of Biostatistics 
7Department of Rehabilitation Services
8Department of Epidemiology and Cancer Control
St. Jude Children's Research Hospital 
262 Danny Thomas Place
Memphis, Tennessee 38105-3678
Telephone: (901) 595-3300
St. Jude Children's Research Hospital
IRB NUMBER: Pro00007558
IRB APPROVAL DATE: 06/30/2023

Revision 5.1 dated 03-21-2023
Protocol document date: 03-21-2023
Contents of this document may not be extracted without permission from the Principal Investigator.
Protocol Summary
TXAKIDS – Tranexamic Acid (TXA) to Reduce Volume of Blood Transfused 
in Pediatric and Young Adult Cancer Patients Undergoing Limb Salvage 
Procedure of a Lower Extremity
Principal Investigator: Michael D. Neel, MD
IND Holder: St. Jude Children’s Research Hospital, IND 147543
Brief Overview: This is a clinical trial evaluating the number of pediatric and young 
adult cancer patients undergoing a limb salvage procedure that frequently requires 
perioperative or post-operative transfusions of blood products. Tranexamic acid 
(TXA) will be tested in pediatric and young adult patients with a history of bone 
malignancy. TXA will be administered perioperatively in a randomized double-blind 
control trial.
Intervention: Eligible participants undergoing limb salvage procedures will be 
randomized to receive either TXA or placebo peri-operatively – one dose at initiation 
of surgical preparation and a second dose 6 hours after the first.
Brief Outline of Treatment Plan: The initial dose of tranexamic acid will be given 
at the initiation of surgical preparation. The second dose will be given 6 hours after 
the first dose (either intraoperatively or post-operatively). All doses will be given 
intravenously at 10 mg/kg with a maximum dose of 1 g. Doses will be double- 
blinded and randomized for each surgical procedure.
Study Design: Prospective Randomized Double-blind Control Trial (TXA versus 
placebo)
Sample Size: We estimate a total accrual of 39 limb salvage patients will be 
needed for the study to yield 38 evaluable subjects.
Data Management: Data management and statistical analysis will be provided 
locally by the Surgery Department and Biostatistics Department at St. Jude 
Children’s Research Hospital.
Human Subjects Per Clinical Trials.gov, pediatric trials have reported minimal 
adverse events using TXA. Patients will be informed of this and other side effects 
during the informed consent discussion. Adverse events will be monitored and 
reported and treated appropriately.
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IRB NUMBER: Pro00007558
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Revision 5.1 dated 03-21-2023
Protocol document date: 03-21-2023
CONTENTS
1.
OBJECTIVES...................................................................................................................1
1.1 Primary Objective.......................................................................................................1
1.2 Secondary Objectives .................................................................................................1
1.3 Exploratory Objectives ...............................................................................................1
2.
BACKGROUND AND RATIONALE.............................................................................2
2.1 Background.................................................................................................................2
2.2 Rationale.....................................................................................................................3
2.3 Background and Rationale for Ancillary and Exploratory Studies ............................4
3.
RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND STUDY 
ENROLLMENT ...............................................................................................................5
3.1. Inclusion Criteria .......................................................................................................6
3.2. Exclusion Criteria ......................................................................................................7
3.3 Research Participant Recruitment and Screening.......................................................7
3.4. Enrollment on Study at St. Jude.................................................................................7
3.5. Procedures for Identifying and Randomizing Research Participants ........................8
4.
TREATMENT PLAN.......................................................................................................8
4.1
Study Treatment.......................................................................................................8
4.2. Dose Modifications....................................................................................................9
4.3. Concomitant Therapy ..............................................................................................10
4.4. Supportive Care .......................................................................................................10
5.
DRUG INFORMATION ................................................................................................11
5.1 Tranexamic Acid (Cykloapron®)..............................................................................11
5.2
Placebo...................................................................................................................12
5.3 Drug Management ....................................................................................................12
6.
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS ...............................12
6.1. Pre-Study Evaluations ...........................................................................................12
6.2. Evaluations During Therapy..................................................................................13
6.3
Response Evaluations ............................................................................................16
6.4. Off-Study Evaluations .............................................................................................16
6.5
Long-Term Follow-up Evaluations .......................................................................16
7.
EVALUATION CRITERIA...........................................................................................16
7.1 Toxicity Evaluation Criteria .....................................................................................16
8.
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF-STUDY 
CRITERIA......................................................................................................................16
8.1. Off-study criteria......................................................................................................16
9.
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS.......................17
9.1. Reporting Adverse Experiences and Deaths to St. Jude IRB ..................................17
9.2 Emergency Unblinding.............................................................................................21
9.3 Reporting to the Sponsor and/or Federal Agencies ..................................................21
9.4 Data and Safety Monitoring Board...........................................................................22
10.
DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY..........22
10.1 Data Collection .......................................................................................................22
10.2 Study Monitoring..................................................................................................23
10.3 Confidentiality........................................................................................................24
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IRB NUMBER: Pro00007558
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Revision 5.1 dated 03-21-2023
Protocol document date: 03-21-2023
11.
STATISTICAL CONSIDERATIONS. ..........................................................................24
11.1 Sample Size Consideration and Randomization....................................................24
11.2 Primary Objective.................................................................................................25
11.3 Secondary Objectives ............................................................................................26
11.4 Exploratory Objectives ..........................................................................................27
11.5 Anticipated Completion Dates................................................................................28
12.
OBTAINING INFORMED CONSENT.........................................................................28
12.1 Informed Consent Prior to Research Interventions ...............................................28
12.2 Consent at Age of Majority ...................................................................................28
12.3 Consent When English is Not the Primary Language ...........................................28
13
REFERENCES ...............................................................................................................30
APPENDIX I:  SCHEDULE OF EVALUATIONS ...................................................................33
APPENDIX II IND DETERMINATION TABLE 1/3...............................................................34
APPENDIX II IND DETERMINATION TABLE 2/3...............................................................35
APPENDIX II IND DETERMINATION TABLE 3/3...............................................................36
APPENDIX III: TESTS PERFORMED FOR GOOD CLINICAL CARE ................................37
APPENDIX IV: RESEARCH TESTS........................................................................................38
APPENDIX V: FUNCTIONAL ASSESSMENT.......................................................................39
APPENDIX VI: RELATION OF STUDY ENDPOINTS TO PROTOCOL OBJECTIVES.....41
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IRB NUMBER: Pro00007558
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1. OBJECTIVES
1.1 Primary Objective
1.1.1. To evaluate the difference in intra-or post-operatively transfused blood volume 
(mL/kg) for patients undergoing limb salvage procedures of the distal femur or proximal 
tibia who are randomized to receive perioperative tranexamic acid (TXA) versus placebo.

Study endpoint: intra- or post-operatively transfused blood volume (mL/kg), 
continuous measurement.
1.2 Secondary Objectives
1.2.1. To evaluate changes in platelets and in hemoglobin from pre-op to post-op level 
for patients randomized to receive perioperative TXA versus placebo.

Study endpoint: changes in platelets and in hemoglobin from pre-op to post-op 
level, continuous measurement.
1.2.2 To evaluate differences in post-operative daily surgical drain output for patients 
randomized to receive perioperative TXA versus placebo.

Study endpoint: postoperative daily surgical drain output, continuous measurement, 
for the duration of the drain.
1.2.3. To evaluate changes in estimated blood loss (EBL) for patients randomized to 
receive perioperative TXA versus placebo.

Study endpoint: estimated blood loss, continuous measurement.
1.2.4. To evaluate the association between the intra-or post-operatively transfused blood 
volume and estimated blood loss (EBL) for patients randomized to receive perioperative 
TXA and placebo, respectively.

Study endpoint: intra- or post-operatively transfused blood volume, continuous 
measurement, until resumption of chemotherapy; estimated blood loss (EBL), 
continuous measurement.
1.3 Exploratory Objectives
1.3.1. To evaluate differences in functional outcomes post-operatively for patients 
randomized to receive perioperative TXA versus placebo.

Study endpoint: Functional Mobility Assessment (FMA), quality of life endpoints 
and Patient-Reported Outcomes Measurement Information System (PROMIS), 
quality of life endpoints.
1.3.2. To explore if significant correlations are observed between parameters reported 
with rotational thromboelastometry (ROTEM®) and EBL and transfusion requirements
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in pediatric and young adult patients undergoing limb salvage procedure who are 
randomized to perioperative TXA versus placebo.

Study endpoint: rotational thromboelastometry (ROTEM), continuous 
measurement; intra- or post-operatively transfused blood volume (mL/kg), 
continuous measurement; estimated blood loss (EBL), continuous measurement.
1.3.3. To evaluate differences in the prevalence and management of wound 
complications such as superficial or periprosthetic infections, wound dehiscence, contact 
dermatitis, post-operative hematomas, or any other clinically significant wound 
complication between patients randomized to receive perioperative TXA versus placebo.

Study endpoint: Number of patients with the wound complications of interest.
2. BACKGROUND AND RATIONALE
2.1 Background
Limb salvage procedures in pediatric and young adult cancer patients are at high risk 
for perioperative bleeding with the resultant need of blood product transfusions. Limb 
salvage procedures may be performed at various anatomic sites with two of the most 
common sites being the distal femur and proximal tibia.
Perioperative bleeding can result in significant post-operative hematoma, which can 
affect wound healing and function. Additionally, platelet-derived growth factors are a 
vital part of the wound healing process. Thrombocytopenia secondary to perioperative 
blood loss contributes to wound healing complications. Delayed healing of wounds can 
adversely affect resumption of chemotherapy and rehabilitation. Patients with 
significant perioperative anemia requiring transfusion are more likely to be tachycardic, 
light-headed and unable to fully participate with rehab thus adversely affecting early 
mobilization and its benefits. The use of tranexamic acid has been shown to reduce the 
incidence of post-operative hematomas27.
The use of antifibrinolytic drugs is one of the strategies for reducing perioperative 
blood loss. Antifibrinolytics such as aminocaproic acid, tranexamic acid, and aprotinin 
have been shown to reduce perioperative blood loss, autologous and/or allogenic blood 
transfusions, and associated costs in pediatric and adolescent patients who underwent 
major spinal, craniofacial or cardiac surgery1-4. Since the restriction of aprotinin use in
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IRB NUMBER: Pro00007558
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T X A KI D S
Pa ge 3
Re visi o n 5. 1 date d 0 3- 2 1- 2 0 2 3
Pr ot oc ol d oc u me nt date: 0 3- 2 1- 2 0 2 3
2 0 0 8, t he m ost c o m m o nl y use d a ntifi bri n ol ytic dr u gs ha ve bee n t he l ysi ne a nal o gs, 
tra ne xa mic aci d ( T X A) a n d ɛ-a mi n oca pr oic  aci d ( E A C A), w hic h i n hi bit t he  
c o n versi o n of plas mi n o ge n t o plas mi n a n d decrease t he de gree of fi bri n ol ysis. T hese 
a ge nts re d uce peri o perati ve bl o o d l oss b y i n hi biti o n of cl ot brea k d o w n 5- 7. Pr os pecti ve, 
ra n d o mize d st u dies ha ve s h o w n t hat t he use of t hese a ge nts i n a d ults ca n be effecti ve i n 
re d uci n g t he peri o perati ve bl o o d l oss a n d tra nsf usi o n re q uire me nts i n t otal j oi nt 
art hr o plast y a n d rec o nstr ucti ve s ur ger y of t he s pi ne 8- 1 2. I n pe diatric patie nts, t he 
efficac y of a ntifi bri n ol ytics s uc h as T X A has bee n de m o nstrate d i n car diac s ur ger y, 
s pi ne def or mities s ur ger y a n d cra ni ofacial s ur ger y 1, 2, 1 3- 1 5. T X A is t he m ost c o m m o n 
a ntifi bri n ol ytic use d w orl d wi de beca use E A C A is n ot a vaila ble i n ma n y c o u ntries 1.
Tra ne xa mic aci d ( T X A) is F D A a p pr o ve d f or pe diatric a n d a d ult he m o p hilia patie nts 
f or t o ot h e xtracti o n at 1 0 m g/ k g/ d ose I V i m me diatel y bef ore s ur ger y, t he n 1 0 
m g/ k g/ d ose I V 3 t o 4 ti mes dail y f or 2 t o 8 da ys. Ra n d o mize d c o ntr olle d trials a n d 
s yste matic re vie ws s u p p ort t he use of T X A t o decrease bl o o d l oss a n d tra nsf usi o n 
re q uire me nts i n pe diatric patie nts u n der g oi n g car diac s ur ger y, s pi ne def or mities 
s ur ger y, cra ni ofacial s ur ger y a n d pe diatric tra u ma. Per Cli nical Trials. g o v, pe diatric 
trials ha ve re p orte d mi ni mal a d verse e ve nts as refere nce d i n A p pe n di x II. S o me 
c o ncer ns e xist a b o ut i ncrease d t hr o m b otic e ve nts wit h t he use of t hese a ge nts, b ut lar ge 
meta-a nal yses s u g gest t hat a ntifi bri n ol ytics ca n be safel y a n d efficaci o usl y e m pl o ye d i n 
pe diatric patie nts.
2. 2 R ati o n ale
C hil dre n, a d olesce nts a n d y o u n g a d ults u n der g oi n g maj or s ur ger y are fre q ue ntl y 
e x p ose d t o a hi g h ris k of peri o perati ve blee di n g wit h c o nc o mita nt re q uire me nt of bl o o d 
pr o d uct tra nsf usi o n. T his i ncreases t he ris k of p ost o perati ve a d verse o utc o mes, 
res ulti n g i n l o n ger le n gt h of h os pital sta y a n d i ncrease d m or bi dit y a n d m ortalit y. T he 
u n derl yi n g mec ha nis ms t hat i ncrease t he blee di n g ris k differ de pe n di n g o n t he t y pe of 
s ur ger y perf or me d. I ncrease d fi bri n ol ysis has bee n i m plicate d as a c o ntri b uti n g fact or 
i n e xcessi ve bl o o d l oss i n pe diatric s pi nal s ur ger y, a d ult art hr o plast y ( T K A) a n d ot her 
maj or s ur geries. St u dies utilizi n g T X A i n pe diatric ort h o pe dic s ur ger y s u p p ort its use t o 
re d uce peri o perati ve bl o o d l oss, drai n o ut p ut a n d p ost- o perati ve he mat o ma. 1, 2, 1 1, 1 5
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: Pr o 0 0 0 0 7 5 5 8
I R B A P P R O V A L D A T E: 0 6 / 3 0 / 2 0 2 3

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Because of the significant risks and complications associated with blood loss and 
allogenic transfusions, efforts to identify safe and effective ways of minimizing blood 
loss perioperatively are crucial. Reducing blood loss and transfusion needs minimizes 
post-operative complications, hospital stay length, and decreases risk of development of 
transfusion related complications such as allergic or transfusion reactions, transfusion- 
related acute lung injury (TRALI), or risk of transmission of blood borne illness18,19.
Maintaining a nearer to normal Hgb and Hct allows the patient to undergo more 
aggressive physical therapy sooner. Higher postoperative Hgb and Hct levels promote 
improved wound healing as well. The use of antifibrinolytic drugs will help to improve 
clinical care and functional outcome of children undergoing limb salvage operations.
The administration of antifibrinolytics, such as TXA and EACA, has been shown to 
reduce bleeding in various surgeries including cardiac, trauma, hip, and knee 
arthroplasty, gynecological, and urologic procedures in adolescents and young adults.1,2 
Since January of 2014 to December of 2017, 39 patients at our institution underwent 
limb-sparing tumor resections of the proximal tibia or distal femur that met the 
inclusion criteria for our proposed study. All 39 patients received either an 
intraoperative or postoperative blood transfusion. The average total blood volume 
transfused was 19.78 mL/kg with a standard deviation of 11.38 mL/kg. The average 
number of transfusions received was 2.95 with a standard deviation of 1.83. The 
average Estimated Blood Loss per Kilogram of Body Weight was 17.84 mL/kg with a 
standard deviation of 16.28 mL/kg.
2.3 Background and Rationale for Ancillary and Exploratory Studies
ROTEM® is an established viscoelastic measurement of hemostasis of whole blood at 
low shear forces. The results of a ROTEM are reported as a reaction curve which shows 
the elasticity over time when a blood clot forms and dissolves. The measurement 
parameters available are as follows:
• CT (Clotting time): The CT is the latency time from adding the start reagent to 
blood until the clot starts to form.
• CFT (Clot formation time) and alpha-angle: The alpha angle is the angle of 
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tangent between the curve while CFT is the time from CT until a clot firmness 
of 20 mm point has been reached. These parameters denote the speed at which a 
solid clot forms and are primarily influenced by platelet, fibrinogen and 
coagulation factors.
• MCF (Maximum clot firmness): MCF is the greatest vertical amplitude 
of the trace. It reflects the absolute strength of the fibrin and platelet clot.
• A10 and A20 values: These values describe the clot firmness (or amplitude) 
obtained after 10 and 20 minutes and provide a forecast on the expected MCF 
value at an earlier stage already.
• LI 30 (Lysis Index after 30 minutes) and ML (Maximum Lysis): The LI30 value 
is the percentage of remaining clot stability in relation to the MCF value at 30 min 
after CT. The ML parameter describes the percentage of lost clot stability (relative 
to MCF, in %) viewed at any selected time point or when the test has been stopped. 
A low LI (X) value or a high ML value indicates hyperfibrinolysis. While in 
normal blood fibrinolysis activity is quite low, in clinical samples a more rapid 
loss of clot stability by hyperfibrinolysis may lead to bleeding complications 
which can be treated by the administration of antifibrinolytic drugs.
Of particular interest for this randomized trial will be the association with the LI30 
to EBL, transfusion requirements and clinical outcomes, because the addition of an 
antifibrinolytic agent like TXA should have a direct impact on this value.
3. RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND STUDY 
ENROLLMENT
According to institutional and NIH policy, the study will accession research 
participants regardless of gender and ethnic background. Institutional experience 
confirms broad representation in this regard.
All clinical and laboratory studies to determine eligibility must be performed within 7 
days prior to enrollment unless otherwise indicated. Laboratory values used to assess 
eligibility must be no older than 7 days at the start of therapy. If a post-enrollment lab
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value is outside the limits of eligibility, or laboratory values are > 7 days old, then the 
following laboratory evaluations must be re-checked within 72 hours prior to initiating 
therapy: CBC with differential, PT, PTT, INR, Fibrinogen, Pregnancy Test and 
Comprehensive Metabolic Panel (CMP).
3.1. Inclusion Criteria
3.1.1. Participant undergoing limb salvage procedure of malignant bone tumor of the 
distal femur or proximal tibia, which typically requires blood transfusions.
3.1.2. Patient under the age of 25
3.1.3. Organ Function Requirements:
a.
Adequate bone marrow function defined as:

Upward trending peripheral absolute neutrophil count (ANC)

Platelet count ≥ 100,000/mm3 (transfusion independent defined 
as no platelets required for 4 days)

Hemoglobin ≥ 8.0 g/dL

No RBC transfusion within 24 hours
b. Adequate renal function defined as:

Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73m2 
OR
Maximum Serum creatinine based on age/gender as follows: (threshold creatinine 
values were derived from the Schwartz formula for estimating GFR) (Schwartz GJ, 
Gauthier B. J Pediatr 1985; 106: 522-6)
Age
Maximum Serum 
Creatinine (mg/dL)
Male
Female
1 day to < 1 years
0.6
0.5
1 to < 2 years
0.6
0.6
2 to < 6 years
0.8
0.8
6 to < 10 years
1.0
1.0
10 to < 13 years
1.2
1.2
13 to < 16 years
1.5
1.4
≥ 16 years
1.7
1.4
c.
Adequate liver function defined as:

Total bilirubin ≤ 1.5x the institutional upper limit of normal 
(IULN) for age

ALT (SGPT) and AST (SGOT) ≤ 2.5x IULN for age (or <5x 
IULN for patients with documented disease involving the liver 
or 10x IULN for patients receiving HDMTX)

Serum albumin > 2 g/dL
d. Adequate coagulation function as defined by International Normalized 
Ratio (INR) ≤ 1.5
3.1.4 Female participants of child-bearing potential (>10 years old) must have a 
negative serum or urine pregnancy test within 72 hours of sedation
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3.2. Exclusion Criteria
3.2.1. Participants whose limb salvage procedure may require significant manipulation 
of major blood vessels.
3.2.2. Participants with known bone marrow deficiency resulting in red blood cell 
deficiency (e.g. Diamond-Blackfan anemia)
3.2.3. Participants receiving erythropoietin-stimulating agents (e.g. epoetin alfa)
3.2.4. Participants with active hemorrhagic cystitis (e.g. alkylator-induced) with gross 
hematuria or >50 RBCs per high powered field on urinalysis
3.2.5. Participants actively receiving all-trans retinoic acid (ATRA) or isotretinoin 
(Accutane)
3.2.6. Participants with known allergies to antifibrinolytics
3.2.7. Participants with known hypercoagulopathies
3.2.8. Personal history of a thrombosis or active thrombus
3.2.9. Participants currently on anticoagulation medications (e.g. warfarin, enoxaparin)
3.2.10. Participants with a history of seizures. Patients with a history of febrile seizure 
are eligible.
3.2.11 Persisting toxicity related to other systemic therapies (e.g. chemotherapy) which 
constitutes an unacceptable safety risk based on the judgment of the PI and/or the primary 
treating physician
3.2.12. Female participants who are currently pregnant or actively breastfeeding.
3.2.13. Female participants who are currently receiving estrogen-based contraception 
therapy.
3.2.14. Inability or unwillingness of research participant or legal guardian/representative 
to give written informed consent.
3.2.15 Participants enrolled in another clinical trial utilizing an IND/IDE experimental 
therapy.
3.2.16 Participants with a history of CNS disease.
3.2.17 Participants with known bleeding disorder.
3.2.18 Participants with known platelet dysfunction.
3.3 Research Participant Recruitment and Screening
This clinical trial will be conducted solely at St. Jude Children's Research Hospital 
(SJCRH). Recruitment will begin in Year 1 and will be completed when a total accrual of 
39 limb salvage patients (to yield 38 evaluable subjects) is reached. Subjects will be 
approached and enrolled during regular surgery consult visits when surgery is being 
planned. We plan on approaching all available eligible participants until enrollment is 
completed. The study will be discussed with each potentially eligible family by the PI 
and/or designee in an unbiased basis until enrollment goals are met.
3.4. Enrollment on Study at St. Jude
A member of the study team will confirm potential participant eligibility as defined in 
Section 3.1 -3.2, complete and sign the ‘Participant Eligibility Checklist’. The completed
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checklist will be faxed to Clinical Trials Operations at 
; followed by a phone 
call to 
 to ensure that the fax is received. Eligibility will be reviewed and 
entered into the Clinical Trials Management System. A research participant-specific 
consent form and assent document, where applicable, will be generated. The signed 
consent/assent form must be faxed or emailed to Clinical Trials Operations (CTO) at 
 
 in order to complete the enrollment. To assist with enrollments and consent 
release, the Clinical Trials Operations (CTO) staff is available Monday through Friday.
After hours and on weekends and holidays, the study team is referred to the CTO 
webpage for additional resources and instructions. Link: 
3.5. Procedures for Identifying and Randomizing Research Participants
Prior to initiating the study, a workshop will be held at SJCRH with team members 
participating. The background to the study, study procedures, consent processes, data 
transfer, and plans to monitor intervention integrity and data quality will be the content 
for that workshop.
Following the workshop and preparation for data collection, screening for eligible 
research participants will begin. Eligibility of newly admitted research participants will 
be confirmed during daily discussions between the PI, designee, and attending physician. 
The PI or designee will then approach the parent or participant regarding the study and 
only after the parent/participant has given permission for such will the PI or designee 
discuss the study with the research participant. If both the research participant and parent 
agree to participate, the randomization plan established by the study biostatistician will 
be accessed according to Section 11.1.
4. TREATMENT PLAN
4.1 Study Treatment
Upon participant enrollment, a SJCRH Pharmaceutical Services Department pharmacist 
will randomize each participant to one of two possible treatment arms (see section 11 for 
randomization).
To allow for the study team and participants to remain blinded to the treatment 
assignment, the study drug will be labeled as Tranexamic Acid/Placebo (TXAKIDS) 
followed by applicable dose and administration instructions.
Study treatment order entry will be managed by study staff according to protocol and 
institutional policies for medication administration. Any modifications to the study 
treatment (frequency or discontinuation) will be done by the study team.
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4.1.1. Active Treatment Arm
At initiation of surgical preparation, participants randomized to the active 
treatment arm will receive tranexamic acid 10 mg/kg (max 1 g), given via 
syringe pump programmed to infuse over 15 minutes. If infused over 15 
minutes, the maximum possible rate will be 67 mg/min (for the maximum 1g 
dose).
4.1.2. Placebo Treatment Arm
At initiation of surgical preparation, participants randomized to the placebo 
treatment arm will receive 0.9% sodium chloride. It will be matched in 
appearance, volume, and administration to the active treatment arm with 
tranexamic acid.
4.1.3
Second Dose
If no unacceptable toxicities occur, a second dose of tranexamic acid/placebo 
(TXAKIDS) 10 mg/kg (max 1 g) IV push over 5 to 15 minutes will be given 6 
hours (with a window of +/- 30 minutes) after the first dose (either intra- or 
post-operatively).
4.2. Dose Modifications
4.2.1. Check BUN/serum creatinine on post-op day 3.
4.2.2. If the patient has a seizure after the first dose and prior to the second dose, the 
second dose will not be given.
4.2.3. An anaphylactic reaction will be considered if the patient experiences any of the 
following 2 symptoms during infusion: nausea/vomiting; hives, pruritis or angioedema; 
dyspnea, wheezing or hypoxemia; syncope; or incontinence. A sudden decrease in 
systolic blood pressure by >30% based on age will also be considered evidence of 
anaphylaxis.
4.2.3.1. In case of anaphylactic reaction, immediately discontinue 
infusion of study agent.
4.2.3.2. Administer diphenhydramine 1 mg/kg IV (max dose 50 mg) and 
epinephrine 1 mg/ml (1:1000) 0.01 mg/kg IM, max dose 0.5 mg.
4.2.3.3. Additional supportive care including oxygen, bronchodilators, 
steroid and vasopressor support may be administered as appropriate.
4.2.3.4. The anesthesia provider will monitor continuously for signs of 
allergic reaction. These signs may include bronchospasm (increased airway 
pressures, difficulty with ventilation), and/or skin rash. Hypotension and 
tachycardia can be seen when an allergic reaction progresses to anaphylactic 
shock and may be suspected for hypotension unresponsive to fluid bolus. If 
an allergic reaction is suspected, a serum tryptase level will be drawn, while
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treatment for allergic reaction (i.e., Epinephrine, anti-histamines) is 
commenced.
4.2.3.5. Medication Hypersensitivity and Anaphylaxis Treatment 
Guidelines can be found at: 
4.3. Concomitant Therapy
4.3.1. Non- Allowed Concomitant Therapies
4.3.1.1. Herbal remedies that may impact coagulation (e.g. St. John’s Wort) or have 
unknown effects on coagulation.
4.3.2. Allowed Concomitant Therapies
4.3.2.1. Patients may receive systemic therapies in accordance with their diagnosis, 
i.e., chemotherapy for patients with malignancy.
4.3.2.2. Patients with a history of reactions to transfusions may receive appropriate 
pre-medications (e.g. acetaminophen, diphenhydramine).
4.3.2.3. Medications that cause temporary impairment of platelet function should be 
used with caution.
4.3.2.4. All concomitant and supportive care medications should be documented.
4.3.3. NSAIDS will be given per standard postoperative pain protocol which is 
immediately after surgery.
4.4. Supportive Care
4.4.1. Central Venous Catheter
While not required for the purposes of this study, many participants will have a central 
venous catheter/line (CVL) in place for intravenous (IV) administration of medications 
and blood products. The CVL may be used for administration of the investigational 
agent/placebo as well as for blood draws, transfusions and other needs based on best 
medical practice.
It is possible that the risk of forming a blood clot in a deep vein or developing problems 
with the central line function may be higher than expected in the group that receives 
TXA. The children in this study are at higher risk of these complications than people in 
previous studies using TXA because of their cancer diagnosis and the fact that they may 
have a central venous line.
4.4.2. Additional Post-Operative Supportive Cares
Participants will receive standard post-operative supportive measures including IV 
hydration, pain medications, nutritional supplementation, and antibiotics per standard 
procedures as indicated by the responsible members of Surgery, Anesthesiology, Critical 
Care, and the primary treating service.
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5.
DRUG INFORMATION
5.1 Tranexamic Acid (Cykloapron®)
Source and Pharmacology: Tranexamic acid is antifibrinolytic, antihemophilic 
and hemostatic agent that forms a reversible complex that displaces plasminogen 
from fibrin resulting in inhibition of fibrinolysis. It also inhibits the proteolytic 
activity of plasmin. By reducing plasmin activity, tranexamic acid also reduces 
activation of complement and consumption of C1 esterase inhibitor (C1-INH), 
thereby decreasing inflammation associated with hereditary angioedema.
Formulation and Stability: Tranexamic acid is available as an intravenous 
solution at a concentration of 1000mg/10mL (10mL vial). Room temperature 
storage is recommended (25oC or 77oF, with temperature excursions permitted 
from 15oC to 30oC (59oF to 86oF)).
Supplier: Commercially available from Pfizer as Cyklokapron® or generic 
manufacturers.
Toxicity: Adverse reactions associated with the injection of Tranexamic acid 
include (frequency not defined): hypotension with rapid IV injection (>1 mL per 
minute), dizziness, allergic dermatitis, menstrual disease (unusual menstrual 
discomfort), diarrhea, nausea, vomiting, and blurred vision. Adverse reactions 
seen with all formulations that were observed to be rare (< 1%), through post 
marketing, and/or case reports include: allergic skin reaction, anaphylactic shock, 
anaphylactoid reaction, cerebral thrombosis, deep vein thrombosis, diarrhea, 
dizziness, nausea, pulmonary embolism, renal cortical necrosis, retinal artery 
occlusion, retinal vein occlusion, seizure, ureteral obstruction, visual disturbances 
(including impaired color vision and vision loss), and vomiting.
Dosage and route of administration including infusion times: The first dose 
will be given at initiation of surgical preparation, and the second dose will be 
given 6 hours after the first dose (either intra- or post-operatively). Dose will be 
given by intravenous push over 5 to 15 minutes at 10mg/kg with a maximum dose 
of 1 g. Dose will not be injected more rapidly than 1 mL per minute to prevent 
hypotension.
Dose rounding at St. Jude will be allowed according to institutional policy (See 
St. Jude Institutional Policy 20.03.004).
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5.2
Placebo
Participants randomized to the placebo arm will receive 0.9% sodium chloride. It 
will be matched in appearance, volume and administration to the active treatment 
arm with Tranexamic acid.
5.3
Drug Management
St. Jude Pharmaceutical Services Department is experienced with managing study 
drugs for clinical trials and will store and control Tranexamic acid and Placebo.
Drug Accountability Record Forms will be maintained to account for the 
inventory and disposition of the investigational agent including receipt, 
dispensing, returns and destruction. Participant specific doses will be ordered by 
investigators in the St Jude electronic medical record after enrollment. All doses 
will be dispensed from the SJCRH pharmacy with labels per our standard SOPs 
including at least participant name, medical record number, dose, and date. If a 
dose cannot be given, it should be returned to the SJCRH Pharmaceutical Services 
Department to be disposed with documentation.
To allow for the study team and participants to remain blinded to the treatment 
assignment, the study drug will be labeled as Tranexamic Acid/Placebo 
(TXAKIDS) followed by applicable dose and administration instructions.
6.
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS
6.1. Pre-Study Evaluations
All entry/eligibility studies must be performed within 1 week prior to entry onto the 
trial (unless otherwise specified).
Pre Study Evaluation – must 
be obtained before enrollment
Within 1 week of enrollment
History and physical exam with 
height (cm), weight (kg), and 
BSA
X
Laboratory Studies: CBC with 
Diff, CMP, Urinalysis, PT, 
PTT, fibrinogen, UA
X
Pregnancy test
Within 48 hours
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6.2. Evaluations During Therapy
6.2.1
Intra-operative labs per Anesthesiology
6.2.1.1. ABGs q1 hour during the case (if arterial line present)
6.2.1.2. Intraoperative transfusion will occur for all patients with a Hb less than 8.0, 
and/or for patients with Hb between 8.0 and 9.0 AND a base deficit greater than or 
equal to -5. The transfusion dose will be 10 mL/kg for patients <30 kg and 1 full unit 
of packed red blood cells for patients >30 kg. A patient may receive multiple 
transfusions.
6.2.1.3. There may be a need for blood transfusion prior to Hb measurement in the 
setting of massive or brisk blood loss. This will be dictated by hemodynamic 
instability and/or obvious massive hemorrhage on the surgical field. Volume 
expanders other than packed red blood cells (i.e., Albumin) may be considered to 
allow time for Hb measurement and will be given at the discretion of the attending 
anesthesiologist.
6.2.2
CMP
6.2.3
Estimated Blood Loss (EBL)
6.2.3.1. At conclusion of surgery
6.2.3.2. EBL measured using Neptune system and weight of surgical laps, calculated 
by Surgery, Anesthesia, and circulating nurse.
6.2.4
CBC
6.2.5
Transfusions (intra-operatively and post-op)
6.2.5.1. Intra-operatively see 6.2.1.2.
6.2.5.2. Post-operative transfusion criteria
6.2.5.3. Hgb <7.0
6.2.5.4. Hgb <8.0 if unstable, tachycardic, or symptomatic, or at clinician’s discretion
6.2.5.5. Volume of and number of patients receiving transfusion
6.2.6
Post-op coags
6.2.7
ROTEM
6.2.8
Management of drain and drain output
6.2.8.1. Drain emptied and recorded at discharge from PACU
6.2.8.2. Measured and recorded when drainage collection system bag is full and/or 
every 8 hours.
6.2.8.3. Drains will be placed to Hemovac or Somavac collection system. “Wall 
suction” will not be utilized.
6.2.8.4. Daily measurement of drain output will be tabulated (over a 24 and 48-
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hour period)
6.2.8.5. Negative pressure wound therapy (if used) “output” will be measured and 
recorded per routine.
6.2.8.6. Patient to remain on antibiotics while drain is in.
6.2.8.7. Drains will be pulled when output is 75 ml or less per 24- hour period
6.2.9
Incisional care
6.2.9.1. Wound care nursing will evaluate the incision at first dressing change and 
at the first post-operative visit then subsequent visits up to 12 weeks post-
op.
6.2.9.2. Starting at the first post-op visit, high risk incisions (patients receiving 
neoadjuvant chemotherapy) will be monitored every 7-14 days up to 12 
weeks post-op or completion of chemotherapy
6.2.10 Incisional healing
6.2.10.1. Presence or absence of dehiscence
6.2.10.2. Presence or absence of clinically significant hematoma
6.2.11 Functional Assessment
6.2.11.1.All patients enrolled on the study will receive a standard physical therapy 
evaluation at the same timepoints (with a window of +/- 2 weeks for all):

weeks post-operatively

3 months post-operatively

6 months post-operatively
6.2.11.2 Additionally, during each physical therapy evaluation, participants will   
complete the FMA, PROMIS, and ROM assessment of the lower extremities.
6.2.11.3 See Appendix V.
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Please see the table below for more detail and obtain other tests as needed for good patient care.
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS
STUDIES TO BE 
OBTAINED
Pre- 
Op
In surgery/PACU/ Post-op
End of 
Study
History
X
with each outpatient visit
X
Physical Exam (Ht, Wt, BSA, 
VS, BMI)
X
with each outpatient visit
X
Type and screen
X
CBC with differential, 
platelets
X
In PACU; daily while inpt; 1 week post- 
op
X
Urinalysis
X
ROTEM
X In PACU
Transfusions (amount 
in cc)
X
Drain output (amount 
in cc)
X, daily until pulled
Incisional healing 
(visualization)
X Post-op
X
Estimated Blood Loss
X At conclusion of surgery
CMP
X
In surgery; daily while inpt; post-op day 
3; 1 week post-op
X
Wound f/u
Daily until hospital discharge.
At week 1 +/- 4 d for all pts; Every 10-14 
days +/- 4 d for “high risk” participants; 
Every 7-10 days +/- 4 d for wounds 
undergoing active management of 
problems; At 6,12 weeks +/- 2 wks. for 
“low risk” participants; All pts. at 2 & 3 
months +/- 3 wks.
X
PT, INR, PTT, fibrinogen
X
PACU; Inpt; 1 week post-op
X
Pregnancy Test*
X
Physical therapy attendance
X
Inpt, 1, 2, 4 and 6 weeks post op +/- 2 
wks; 2 and 3 mos. post op +/- 2 wks
X
Functional Mobility 
Assessment (FMA)
6 wks., 3 mos. post op +/- 2 wks
X
PROMIS
X
6 wks., 3 mos. post op +/- 2 wks
X
ROM
X
6 wks., 3 mos. post op +/- 2 wks
X
* The St. Jude IRB requires that a female patient of childbearing potential must have a negative 
pregnancy test as a condition of clinical research eligibility.
Obtain other studies as needed for good patient care. End of study for each participant 
will be after the 6-month evaluation (+/- 1 month) has been completed.
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6.3 Response Evaluations
6.3.1. Wound care follow up to include photo documentation for anyone on 
chemotherapy or undergoing radiation therapy or who develops a wound problem.
6.3.2. For high risk participants who are not at SJ weekly, local wound care must be 
found. These individuals must provide SJ with photo documentation of wound care 
follow up.
6.3.3. Wound complications will be graded using CTC AE version 5.0.
6.4. Off-Study Evaluations
6.4.1. Wound evaluation
6.4.2. Functional assessment by physical therapy
6.5 Long-Term Follow-up Evaluations
None.
7.
EVALUATION CRITERIA
7.1. Toxicity Evaluation Criteria
The Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 will be 
used for toxicity and performance reporting. A copy of CTCAE Version 5.0 can be 
downloaded from the CTEP home page 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_ 
Quick_Reference_8.5x11.pdf
8.
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND 
OFF-STUDY CRITERIA
8.1. Off-study criteria
8.1.1. Death
8.1.2. Lost to follow-up
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8.1.3. Request of the Patient/Parent
8.1.4. Completion of all study-related treatment and follow-up
8.1.5. Discretion of the study PI
8.1.6. Found after enrollment to be ineligible
8.1.7. Seizure
8.2. Off-therapy criteria
8.2.1. Development of unacceptable toxicity during treatment:
8.2.1.1. Acute kidney injury (defined by doubling of creatinine)
8.2.1.2.  Anaphylaxis (grade 3 or 4).
8.2.1.3.  Seizure
8.2.2. Did not receive second dose of TXA/placebo due to unacceptable toxicity
8.2.3. Completed both doses of TXA/placebo
9.
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS
9.1. Reporting Adverse Experiences and Deaths to St. Jude IRB
9.1.1. Only “unanticipated problems involving risks to participants or others” referred to 
hereafter as “unanticipated problems” are required to be reported to the St. Jude IRB 
promptly, but in no event later than 10 working days after the investigator first learns of 
the unanticipated problem. Only adverse events that constitute unanticipated problems 
are reportable to the St. Jude IRB. The Common Terminology Criteria for Adverse 
Events (CTCAE) version 5 will be used to grade adverse events. As further described in 
the definition of unanticipated problem, this includes any event that in the PI’s opinion 
was:

Unexpected (in terms of nature, severity, or frequency) given (1) the 
research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and informed 
consent document, as well as other relevant information available 
about the research; (2) the observed rate of occurrence (compared to a 
credible baseline for comparison); and (3) the characteristics of the 
subject population being studied; and

Related or possibly related to participation in the research; and
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
Serious; or if not serious suggests that the research places subjects or 
others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized.
Unrelated, expected deaths do not require reporting to the IRB. Though death is 
“serious”, the event must meet the other two requirements of “related or possibly 
related” and “unexpected/unanticipated” to be considered reportable.
Deaths meeting reporting requirements are to be reported immediately to the St. 
Jude IRB, but in no event later than 48 hours after the investigator first learns of 
the death.
9.1.2. The following definitions apply with respect to reporting adverse experiences:
9.1.2.1. Serious Adverse Event: Any adverse event temporally associated with the 
subject’s participation in research that meets any of the following criteria:

results in death;

is life-threatening (places the subject at immediate risk of death 
from the event as it occurred);

requires inpatient hospitalization or prolongation of existing 
hospitalization;

results in a persistent or significant disability/incapacity;

results in a congenital anomaly/birth defect; or

any other adverse event that, based upon appropriate medical 
judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other 
outcomes listed in this definition (examples of such events include: 
any substantial disruption of the ability to conduct normal life 
functions, allergic bronchospasm requiring intensive treatment in 
the emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse), a congenital anomaly/birth 
defect, secondary or concurrent cancer, medication overdose, or is 
any medical event which requires treatment to prevent any of the 
medical outcomes previously listed.
9.1.2.2. Unexpected Adverse Event:

Any adverse event for which the specificity or severity is not 
consistent with the protocol-related documents, including the 
applicable investigator brochure, IRB approved consent form, 
Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) application, or other relevant sources of 
information, such as product labeling and package inserts; or if it 
does appear in such documents, an event in which the specificity,
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severity or duration is not consistent with the risk information 
included therein; or

The observed rate of occurrence is a clinically significant increase 
in the expected rate (based on a credible baseline rate for 
comparison); or

The occurrence is not consistent with the expected natural 
progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s 
predisposing risk factor profile for the adverse event.
9.1.2.3. Internal Events: Events experienced by a research participant enrolled at a 
site under the jurisdiction of St. Jude IRB single-center research projects.
9.1.2.4. Unanticipated Problem Involving Risks to Subjects or Others: An 
unanticipated problem involving risks to subjects or others is an event which was 
not expected to occur and which increases the degree of risk posed to research 
participants. Such events, in general, meet all of the following criteria:

unexpected;

related or possibly related to participation in the research; and

suggests that the research places subjects or others at a greater risk 
of harm (including physical, psychological, economic, or social 
harm) than was previously known or recognized. An unanticipated 
problem involving risk to subjects or others may exist even when 
actual harm does not occur to any participant.
Although some adverse events will qualify as unanticipated problems involving risks to 
subjects or others, some will not; and there may be other unanticipated problems that go 
beyond the definitions of serious and/or unexpected adverse events. Examples of 
unanticipated problems involving risks to subjects or others include:

Improperly staging a participant’s tumor resulting in the participant 
being assigned to an incorrect arm of the research study;

The theft of a research computer containing confidential subject 
information (breach of confidentiality); and

The contamination of a study drug. Unanticipated problems generally 
will warrant consideration of substantive changes in the research 
protocol or informed consent process/document or other corrective 
actions in order to protect the safety, welfare, or rights of subjects or 
others.
9.1.2.5 There will be an assessment for the existence of adverse events with each 
study participant encounter, i.e. during each history and/or physical, as depicted in 
Appendix I. The study team will capture all Grade 3-5 adverse events, including 
lab toxicities. All adverse events will be assessed for seriousness, grade,
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attribution/ causality, and duration. Adverse events will be recorded in the 
database and reported as per institutional policy. The study team and the PI will 
review adverse events/toxicities during regular study team meetings. Once 
adverse events/toxicities have been reviewed, the PI will sign and date a study AE 
document.
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9.2 Emergency Unblinding
In the case of a medical emergency or in the event of a serious medical condition, 
when knowledge of the investigational product is essential for the clinical 
management or welfare of the participant, an investigator or other physician managing 
the participant may decide to unblind that participant’s treatment code.
The physician managing the medical emergency or serious condition should attempt 
to contact the principal investigator to discuss options prior to unblinding, and the 
principal investigator should approve the unblinding, when applicable. However, 
ensuring patient safety is the primary objective when the decision to unblind the 
treatment assignment is made.
The principal investigator or designated study personnel will request to unblind the 
participant’s treatment arm. The principal investigator or treating clinician will 
contact St. Jude Pharmaceutical Services Department to receive the unblinding 
information.
All occurrences of emergency unblinding will be reported to the IRB according to the 
criteria established in protocol section 9.0, the DSMB, and the FDA, when applicable. 
In a majority of cases, emergency unblinding will occur while managing a serious 
adverse event (SAE), and will therefore be reported with the SAE. If the unblinding 
event is not directly associated with an SAE, the same timeline and mechanism for 
reporting SAEs will be used to notify the IRB of the event (section 9.1).
9.3 Reporting to the Sponsor and/or Federal Agencies
9.3.1. Notification of Federal Agencies by Investigator
Any unanticipated fatal or unanticipated life-threatening event judged by the PI to be at 
least possibly due to the study treatment, will be reported to the DSMB by e-mail and the 
FDA by telephone or fax as soon as possible but no later than seven calendar days after 
notification of the event and followed by a written safety report as complete as possible 
within eight additional calendar days (i.e., full report 15 calendar days total after 
notification of event).
Unanticipated, non-fatal and non-life-threatening adverse events that occur in on-study 
patients and that are considered due to or possibly due to the investigational agent, will be 
reported to the FDA by written safety report as soon as possible but no later than 15 
calendar days of the notification of the occurrence of the event. Expected SAEs, even 
unexpected fatal SAEs, considered by the PI to be not related to the study, will be
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reported to the FDA in the Annual Review Report along with non-serious AEs. All FDA 
correspondence and reporting will be conducted through the St. Jude Office of 
Regulatory Affairs.
Copies of all correspondence to the St. Jude IRB, including SAE reports, are provided to 
the St. Jude Regulatory Affairs office by the St. Jude study team. FDA-related 
correspondence and reporting will be conducted through the Regulatory Affairs office.
9.3.2 Recording Adverse Events and Serious Adverse Events
Adverse events and serious adverse events will be recorded using the Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0.
9.4 Data and Safety Monitoring Board
This study has been referred to the St. Jude Data and Safety Monitoring Board (DSMB) for 
regular monitoring and has been sent to the DSMB. The DSMB is charged with advising 
the Director and other senior leaders of St. Jude Children’s Research Hospital (SJCRH) on 
the safety of clinical protocols being conducted by SJCRH investigators and on their 
continuing scientific validity. The DSMB will monitor this protocol every six months for 
safety events/ toxicity. Refer to the DSMB Charge and Criteria for Protocol Referral for 
more information regarding DSMB review.
10. DATA COLLECTION, STUDY MONITORING, AND 
CONFIDENTIALITY
10.1 Data Collection
Electronic case-report forms (e-CRFs) will be completed by the St. Jude Clinical 
Research Associates (CRAs). Data from the participant’s medical record will be entered 
directly into a secure Trial Master database developed and maintained by St. Jude 
Clinical Research Informatics.
Data collection will be performed by the CRA working in the Department of Surgery. 
Protocol-specific data and adverse events will be recorded by the CRA in the Trial 
Master database. All questions will be directed to the attending physician and/or PI and 
will be reviewed at regularly scheduled working meetings. Adverse event/toxicity data to 
be collected and entered into the Trial Master database include: Time point; AE category; 
Grade; Onset date; Is AE permanent (yes or no); Resolved date; Relationship; Action; 
Outcome; Was AE serious as defined by the protocol (yes or no); AE expected (yes or
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no); AE result in off treatment (yes or no); Was this an unanticipated problem (yes or no); 
Comments.
Regular summaries of toxicity and protocol events will be generated for the PI and the 
Department of Biostatistics to review. Participants will be followed for up to 6 months 
post-op.
10.2 Study Monitoring
This study is considered high risk (HR-3) for monitoring purposes. Protocol and 
regulatory compliance, including essential regulatory documentation, will be assessed as 
well as the accuracy and completeness of all data points relating to the primary and 
secondary objectives semi-annually. If the study design has strata, accrual will be 
tracked continuously. The first two enrollees will be monitored and 15 % of the study 
enrollees thereafter, semi-annually.
The PI and study team are responsible for protocol and regulatory compliance, and for 
data accuracy and completeness. The study team will meet at appropriate intervals to 
review case histories or quality summaries on participants and retain copies of the 
minutes which are signed by the PI.
Clinical Trials Operations (CTO) will verify informed consent documentation and 
eligibility status on 100% of St. Jude participants within 5 working days of enrollment 
completion.
Overall study conduct, compliance with primary and secondary objectives, age of 
majority consenting, safety assessments and reporting, and the timeliness and accuracy of 
database entries are monitored routinely.
Study documents routinely monitored on selected participants include medical records, 
database entries, study worksheets, and case report forms. Study documents are 
monitored for participant status, demographics, staging, subgroup assignment, treatments, 
investigational drug accountability, evaluations, responses, participant protocol status,
off-study and off-therapy criteria, and for all other specifics as detailed in a separate 
study-specific monitoring plan. The study-specific monitoring plan may be revised over 
time, to adapt monitoring frequency and/ or intensity to a changing environment when 
appropriate (for example: new safety signals; positive history of compliance; all 
participants are in long term follow-up; or the enrollment period has ended).
The recording and reporting of Adverse Events, Serious Adverse Events (SAEs), and 
Unanticipated Problems (UPs) to include type, grade, attribution, duration, timeliness and
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appropriateness will be reviewed by the Monitor/ CRM. The CRM will generate a formal 
report which is shared with the Principal Investigator (PI), study team and the Internal 
Monitoring Committee (IMC).
Continuing reviews by the Institutional Review Board (IRB) and Clinical Trials- 
Scientific Review Committee (CT-SRC) will occur at least annually. In addition, 
unanticipated problems are reviewed in a timely manner by the IRB.
10.3 Confidentiality
Subjects’ information will be kept in secure files on secure, password protected 
computers. Only investigators and study staff will have access to PHI. PHI will not be 
shared with anyone outside SJCRH. When the data are published, no identifiers will be 
used that can possibly link the reported information to a given subject.
The medical records of study participants may be reviewed by the St. Jude IRB, FDA, 
clinical research monitors, etc.
11. STATISTICAL CONSIDERATIONS
11.1
Sample Size Consideration and Randomization
This study will be conducted as a randomized, placebo-controlled double-blind trial of 
the administration of TXA vs. placebo prior to a limb salvage procedure. The primary 
objective will be to evaluate if TXA will reduce the proportional blood transfusion 
volume and EBL. The sample size is calculated based on the hypothesis that the TXA 
administration will reduce the average total volume of red blood cell transfused per 
kilogram of body weight by 40% relative to the average total volume of red blood cells 
transfused of the placebo group. Our historical data should be representative of our 
proposed placebo group, and historically, the average total red blood cell volume 
transfused per kilogram of body weight is 19.78 mL/kg + 11.38. The distribution of the 
intra-or post-operatively transfused blood volume is normally distributed after log(1+x) 
transformation (mean=2.906, sd = 0.507). We use the two-sample t-test with unequal 
variances to access the primary objective through the log(1+x) transformation of 
proportional blood transfusion volume.
We calculate the sample size with the two-sided two-sample t-test with unequal 
variances for the log(1+x) transformation proportional blood transfusion volume. 
Nineteen patients in each group are sufficient to detect a 40% decrease of log(1+x) 
transformation of proportional blood transfusion volume (mean=2.435, sd = 0.488) with
0.8 power and type I error 0.05. It can be safely assumed that the number of patients who
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do not require blood transfusion is less than 5%. Given the sample size, we do not 
anticipate the blood transfusion volume will have substantial ties at 0.
Randomization will be performed in the SJCRH Pharmaceutical Services Department by 
a pharmacist using the randomization program developed by the Department of 
Biostatistics.26 The drug is clear and will be given IV. The people who would determine 
the transfusion volume are blinded to the treatment. The randomization is stratified by the 
variable pre-operative weight that leads to two strata: pre-operative weight > 45.2 kg and 
pre-operative weight <=45.2 kg, where 45.2 kg is the median of pre-operative weight in 
the historical control data underwent limb-sparing tumor resections of the proximal tibia 
or distal femur. The assignment ratio of the TXA group to the placebo group is 1:1.
The patients who receive only one dose due to anaphylaxis (grade 3 or 4) or seizure will 
be removed from the evaluation of all objectives. The anticipated rate of each toxicity is 
about 1%. However, the descriptive statistics will be calculated for these patients who 
receive only one dose, e.g., adverse events and endpoints in all the objectives. The 
expected accrual number for our study will be 39 patients (to yield 38 evaluable 
subjects).
Unacceptable toxicities consist of acute kidney injury (defined by doubling of creatinine) 
or anaphylaxis (grade 3 or 4) or thrombotic event or seizure. The anticipated rate of each 
toxicity is about 1%. Thrombotic events occurring six weeks beyond the time of surgery 
will not be considered related to TXA administration. A heuristic approach is used to 
monitor each of the three toxicities in the TXA group. For each toxicity, starting from the 
3rd patient, if the number of patients with any toxicity is equal to or larger than 3, the 
study accrual will be paused and amendments to the protocol will be discussed with the 
IRB. This monitoring rule yields the largest type-I error rate 0.044 when the 20th (one 
patient is removed due to not receiving the 2nd dose) patient show the toxicity (the 20th 
patient and any two previous patients in the TXA group).
11.2 Primary Objective
11.2.1. To evaluate the difference in intra-or post-operatively transfused blood volume 
(mL/kg) for patients undergoing limb salvage procedures who are randomized to 
receive perioperative tranexamic acid (TXA) versus placebo.
The intra-or post-operative volumes of transfused blood for both the TXA treated 
group and placebo group will be estimated with a two-sided 95% confidence 
interval. The blood volumes transfused per kilogram of body weight of the two 
groups (TXA vs. Placebo) will be evaluated using a two-sided student’s t-test after 
log(1+x) transformation.
11.2.2. Accrual and study duration
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This study will be conducted solely at St. Jude Children’s Research Hospital 
(SJCRH). According to the historical data, during January of 2014 through 
December of 2017 (48 months), 39 patients underwent limb-sparing tumor 
resections of the proximal tibia or distal femur that met the inclusion criteria for 
our proposed study. These preliminary data suggest that the randomized controlled 
trial with 39 patients (TXA vs. Placebo) would be feasible in a 48 months period 
of time.
11.3
Secondary Objectives
11.3.1. To evaluate changes in platelets and hemoglobin from pre-op to post-op level for 
patients randomized to receive perioperative TXA versus placebo.
Summary statistics will be provided for the changes in platelet level and decline in 
hemoglobin from pre-op to post-op level, for both the TXA and placebo group.
Two sample t-test or Wilcoxon rank sum test will be used to compare the 
differences between the two groups. Multiple comparison correction might be used 
for p-values to address the multiple testing issues due to measurements at multiple 
time points.
11.3.2. To evaluate differences in post-operative daily surgical drain output for patients 
randomized to receive perioperative TXA versus placebo.
Summary statistics will be provided for postoperative daily surgical drain output 
(in milliliters per 24 hour period for the duration of the drain) for each group. The 
group difference will be compared using two-sample t-test or Wilcoxon rank sum 
test depending on the distribution of the observed data. Multiple comparison 
correction might be used for p-values to address the multiple testing issues due to 
measurements at multiple time points.
11.3.3. To evaluate changes in estimated blood loss (EBL) for patients randomized to 
receive perioperative TXA versus placebo.
The EBL for pre-op to post-op level, for both the TXA treated group and placebo 
group will be estimated with a two-sided 95% confidence interval. The EBL of the 
two groups (TXA vs. Placebo) will be evaluated using a two-sample t-test or 
Wilcoxon rank sum test depending on the distribution of the observed data.
11.3.4. To evaluate the association between the intra-or post-operatively transfused 
blood volume and estimated blood loss (EBL) for patients randomized to receive 
perioperative TXA and placebo, respectively.
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Regression model will be used to access the correlation between the log 
transformed intra-or post-operatively transfused blood volume and EBL.
11.4
Exploratory Objectives
11.4.1. To evaluate differences in functional outcomes post-operatively for patients 
randomized to receive perioperative TXA versus placebo.
Summary statistics will be provided for postoperative functional assessment scores 
(at each physical therapy session and at timepoints 6, 12, and 24 weeks) for each 
group. The group difference will be compared using two-sample t-test or Wilcoxon 
rank sum test, depending on the distribution of the observed data. Multiple 
comparison correction might be used for p-values to address the multiple testing 
issues due to measurements at multiple time points. We will calculate the missing 
proportions of the functional outcomes at every follow-up.
11.4.2. To explore if significant correlations are observed between parameters reported 
with rotational thromboelastometry (ROTEM®) and EBL and transfusion
requirements in pediatric and young adult patients undergoing limb salvage 
procedure who are randomized to perioperative TXA versus placebo.
Multiple regression model is used to analyze the association between each 
measurement of rotational thromboelastometry (ROTEM®) and EBL and 
transfusion requirements while accounting for possible covariates. Multiple 
comparison correction might be used for p-values to address the multiple testing 
issues due to multiple measurements of ROTEM. Multivariate regression model 
may be used to study the associations between multiple measurements of ROTEM 
and EBL and transfusion requirements jointly. We will calculate the missing 
proportions of ROTEM at every follow-up.
11.4.3. To evaluate differences in the prevalence and management of wound 
complications such as superficial or periprosthetic infections, wound dehiscence, 
contact dermatitis, post-operative hematomas, or any other clinically significant 
wound complication between patients randomized to receive perioperative TXA 
versus placebo.
The proportions of observed wound complications and proportions of observed 
interventions will be estimated for both the TXA group and placebo group with 
95% confidence intervals and compared between these two groups using Fisher’s 
Exact Test. We will calculate the missing proportions of wound complications at
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every follow-up. Multiple comparison correction might be used for p-values to 
address the multiple testing issues due to measurements at multiple time points.
11.5 Anticipated Completion Dates
12 OBTAINING INFORMED CONSENT
12.1
Informed Consent Prior to Research Interventions
Informed consent must be obtained from the participant family prior to 
performing any non-standard of care research tests for this study.
12.2
Consent at Age of Majority
The age of majority in the state of Tennessee is 18 years old. Research 
participants must be consented at the next clinic visit after their 18th birthday.
12.3
Consent When English is Not the Primary Language
When English is not the patient, parent, or legally authorized representative’s 
primary language, the Social Work department will determine the need for an 
interpreter. This information will be documented in the participant’s medical 
record. Either a certified interpreter or the telephone interpreter’s service will be 
used to translate the consent information. The process for obtaining an interpreter 
and for the appropriate use of an interpreter is outlined on the Interpreter Services, 
OHSP, and CTO websites.
Additionally, the study participant family will be given a written short form 
consent in their native language during the initial consenting process which 
clarifies that the study is research. The study team will request a summary of the 
protocol in the participant’s native language (long-form consent) and obtain re- 
consent when the more detailed native language information is available.
Anticipated Study Completion Date 03/2025
Anticipated Primary Completion Date: 09/2024
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13 REFERENCES
1.
Faraoni D, Goobie SM. The efficacy of antifibrinolytic drugs in children undergoing 
noncardiac surgery: a systematic review of the literature. Anesthesia and analgesia 
2014;118:628-36.
2.
Sethna NF, Zurakowski D, Brustowicz RM, Bacsik J, Sullivan LJ, Shapiro F. Tranexamic 
acid reduces intraoperative blood loss in pediatric patients undergoing scoliosis surgery. 
Anesthesiology 2005;102:727-32.
3.
Chauhan S, Bisoi A, Modi R, Gharde P, Rajesh MR. Tranexamic acid in paediatric 
cardiac surgery. The Indian journal of medical research 2003;118:86-9.
4.
Zonis Z, Seear M, Reichert C, Sett S, Allen C. The effect of preoperative tranexamic acid 
on blood loss after cardiac operations in children. The Journal of thoracic and cardiovascular 
surgery 1996;111:982-7.
5.
Hardy JF, Desroches J. Natural and synthetic antifibrinolytics in cardiac surgery. 
Canadian journal of anaesthesia = Journal canadien d'anesthesie 1992;39:353-65.
6.
Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. 
Drugs 1999;57:1005-32.
7.
Cardone D, Klein AA. Perioperative blood conservation. European journal of 
anaesthesiology 2009;26:722-9.
8.
Eubanks JD. Antifibrinolytics in major orthopaedic surgery. The Journal of the American 
Academy of Orthopaedic Surgeons 2010;18:132-8.
9.
Alshryda S, Sarda P, Sukeik M, Nargol A, Blenkinsopp J, Mason JM. Tranexamic acid in 
total knee replacement: a systematic review and meta-analysis. The Journal of bone and joint 
surgery British volume 2011;93:1577-85.
10.
Cid J, Lozano M. Tranexamic acid reduces allogeneic red cell transfusions in patients 
undergoing total knee arthroplasty: results of a meta-analysis of randomized controlled trials. 
Transfusion 2005;45:1302-7.
11.
Zufferey P, Merquiol F, Laporte S, et al. Do antifibrinolytics reduce allogeneic blood 
transfusion in orthopedic surgery? Anesthesiology 2006;105:1034-46.
12.
Cheriyan T, Maier SP, 2nd, Bianco K, et al. Efficacy of tranexamic acid on surgical 
bleeding in spine surgery: a meta-analysis. The spine journal : official journal of the North 
American Spine Society 2015;15:752-61.
13.
Faraoni D, Goobie SM. New insights about the use of tranexamic acid in children 
undergoing cardiac surgery: from pharmacokinetics to pharmacodynamics. Anesthesia and 
analgesia 2013;117:760-2.
14.
Goobie SM, Meier PM, Sethna NF, et al. Population pharmacokinetics of tranexamic acid 
in paediatric patients undergoing craniosynostosis surgery. Clinical pharmacokinetics 
2013;52:267-76.
15.
Stricker PA, Gastonguay MR, Singh D, et al. Population pharmacokinetics of - 
aminocaproic acid in adolescents undergoing posterior spinal fusion surgery. British journal of 
anaesthesia 2015;114:689-99.
16.
Martin K, Breuer T, Gertler R, et al. Tranexamic acid versus varepsilon-aminocaproic 
acid: efficacy and safety in paediatric cardiac surgery. European journal of cardio-thoracic
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surgery : official journal of the European Association for Cardio-thoracic Surgery 2011;39:892- 
7.
17.
Breuer T, Martin K, Wilhelm M, et al. The blood sparing effect and the safety of 
aprotinin compared to tranexamic acid in paediatric cardiac surgery. European journal of cardio- 
thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 
2009;35:167-71; author reply 71.
18.
Sharma S, Sharma P, Tyler LN. Transfusion of blood and blood products: indications and 
complications. American family physician 2011;83:719-24.
19.
Sandler SG, Yu H, Rassai N. Risks of blood transfusion and their prevention. Clinical 
advances in hematology & oncology : H&O 2003;1:307-13.
20.
Marchese VG, Rai SN, Carlson CA, Hinds PS, Spearing EM, Zhang L, Callaway L, Neel 
MD, Rao BN, Ginsberg JP. Assessing functional mobility in survivors of lower-extremity 
sarcoma: reliability and validity of a new assessment tool. Pediatric Blood Cancer. 2007; 
49:183-189.
21.
Makhni EC, Meadows M, Hamamoto JT, Higgins JD, Romeo AA, Verma NN. Patient 
Reported Outcomes Measurement Information System (PROMIS) in the upper extremity: the 
future of outcomes reporting? Journal of Shoulder and Elbow Surgery. 2017; 26, 352-357.
22.
DeWitt EM, Stucky BD, Thissen D, Irwin DE, Langer M, Varni JW, Lai J-S, Yeatts KB, 
DeWalt DA. Construction of the eight-item patient-reported outcomes measurement information 
system pediatric physical function scales: built using item response theory. Journal of Clinical 
Epidemiology. 2011; 64:794-804.
23.
Hinds PS, Nuss SL, Ruccione KS, Withycombe JS, Jacobs S, Deluca H, Faulkner C, Liu 
Y, Cheng YI, Gross HE, Wang J, DeWalt DA. PROMIS pediatric measures in pediatric 
oncology: valid and clinically feasible indicators of patient-reported outcomes. Pediatric Blood 
Cancer. 2013; 60:402-408.
24.
Shaw BE, Syrjala KL, Onstad LE, Chow EJ, Flowers ME, Jim H, Baker KS, Buckley S, 
Fairclough DL, Horowitz MM, Lee SJ. PROMIS measures can be used to assess symptoms and 
function in long-term hematopoietic cell transplantation survivors. Cancer. 2017; 000.
25.
Hancock KJ, Glass N, Anthony CA, Hettrich CM, Albright J, Amendola A, Wolf BR, 
Bollier M. Performance of PROMIS for healthy patients undergoing meniscal surgery. The 
Journal of Bone and Joint Surgery. 2017; 99:954-958.
26.
Zelen, M A new design for randomized clinical trials. New Engl J Med. 1979;300:1242- 
1245.
27.
Losak et al, Acta Chir Orthop Traumatol cech, 2017:84(4),254-262
28.
Couturier R, Rubatti M, Credico C, Louvain-Quintard V, Anerkian V, Doubine S, Vasse 
M, Grassin-Delyle S. Continuous or discontinuous tranexamic acid effectively inhibits 
fibrinolysis in children undergoing cardiac surgery with cardiopulmonary bypass. Blood Coagul 
Fibrinolysis. 2014 Apr;25(3):259-65.
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29.
Brum MR, Miura MS, Castro SF, Machado GM, Lima LH, Lubianca Neto JF. 
Tranexamic acid in adenotonsillectomy in children: a double-blind randomized clinical trial. Int J 
Pediatr Otorhinolaryngol. 2012 Oct;76(10):1401-5.
30.
Verma K, Errico T, Diefenbach C, Hoelscher C, Peters A, Dryer J, et al. The relative 
efficacy of antifibrinolytics in adolescent idiopathic scoliosis: a prospective randomized trial. 
The Journal of bone and join surgery American volume. 2014 May 21;96(10):e80. Epub 
2014/05/31.
31.
Goobie SM, Meier PM, Pereira LM, McGowan FX, Prescilla RP, Scharp LA, Rogers GF, 
Proctor MR, Meara JG, Soriano SG, Zurakowski D, Sethna NF. Efficacy of tranexamic acid in 
pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial. Anesthesiology. 
2011 Apr;114(4):862-71.
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APPENDIX I: SCHEDULE OF EVALUATIONS
Schedule of Study Evaluations
Event
Pre-OP
PACU
1-6
days 
(if inpt)
1
week
2
weeks
4
weeks
6
weeks
2
months
3
months
6
months
CBC, Differentials, Platelets
x
x
x
x
x
ROTEM
x
Drain Output
x
x
x
Wound f/u
x
x
x
x
x
x
x
x
x
Physical Therapy Attendance
x
x
x
x
x
x
x
x
x
CMP
x
x
x
x
PT, PTT, INR, Fibrinogen
x
x
x
x
x
History
x
x
x
x
x
x
x
x
x
Physical (Ht, Wt, BSa, VS, 
BMI)
x
x
x
x
x
x
x
x
x
Type and Screen
x
Urinalysis
x
Pregnancy Test
x
FMA
x
x
x
PROMIS
x
x
x
x
ROM
x
x
x
x
EBL
x
Evaluation for Adverse Events
x
x
x
x
x
x
x
x
x
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APPENDIX II IND DETERMINATION TABLE 1/3
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Protocol document date: 03-21-2023
Agent
FDA
Indication
Pediatric Indications
Pediatric Trials
Pediatric 
Dosing
FDA Label 
Dose
Additional 
Safety Info
Reference
(clinicaltrials.gov)
Tranexamic
Immediately
Limited use in pediatric
Same as adult
FDA approved
FDA Approved Labeling
Acid
before tooth
patients with hemophilia,
dosing
dose = 10 mg/kg IV
extraction and
principally in connection
Following tooth
following for 2 to
with tooth extraction. The
extraction, 10
8 days in
limited data suggest that
mg/kg IV body
patients with
dosing instructions for
three to four times
hemophilia.
adults can be used for
daily, may be used
pediatric patients needing
for 2 to 8 days.
CYKLOKAPRON therapy.
Tranexamic
NCT01141127
10 mg/kg IV at
Couturier R, Rubatti M, Credico C,
Acid
Prospective,
beginning, middle
Louvain-Quintard V, Anerkian V,
randomized parallel
and end of surgery
Doubine S, Vasse M, Grassin-
assignment of two
-or-
Delyle S. Continuous or
dosing regimens of
Loading Dose=10
discontinuous tranexamic acid
tranexamic acid in
mg/kg IV followed
effectively inhibits fibrinolysis in
pediatric cardiac
by maintenance
children undergoing cardiac
surgery (n=18 from
dose = 1mg/kg/hr
surgery with cardiopulmonary
12 mo-12 yrs )
until end of surgery
bypass. Blood Coagul Fibrinolysis.
2014 Apr;25(3):259-65. doi:
10.1097/MBC.0000000000000051.
Tranexamic
NCT01228136
10 mg/kg IV, 30 min
Drug Intolerance or
Brum MR, Miura MS, Castro SF,
Acid,
Prospective,
before surgery then
adverse effects
Machado GM, Lima LH, Lubianca
Placebo
(NS)
randomized, double-
blind comparison of
q 8 hrs x 2 doses
were not observed.
Neto JF. Tranexamic acid in
adenotonsillectomy in children: a
tranexamic acid or
double-blind randomized clinical
placebo in pediatric
trial. Int J Pediatr Otorhinolaryngol.
adenotonsillectomy
2012 Oct;76(10):1401-5. doi:
10.1016/j.ijporl.2012.04.028. Epub
2012 Jun 16.
Tranexamic
NCT02188576
Loading Dose = 50
Acid
Prospective, Phase 4,
mg/kg IV or 10
randomized, parallel
mg/kg IV with
assignment of two
maintenance of 5
dosing regimens in
mg/kg/h IV during
pediatric (3 mo-6 yrs)
surgery
craniosynostosis
surgery
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Revision 5.1 dated 03-21-2023
Protocol document date: 03-21-2023
Agent
FDA
Indication
Pediatric 
Indications
Pediatric Trials
Pediatric 
Dosing
FDA
Label 
Dose
Additional Safety Info
Reference
(clinicaltrials.gov)
Tranexamic
NCT00958581
Loading Dose=10
Ongoing bleeding in one
Verma K, Errico T, Diefenbach C, Hoelscher C,
Acid,
Prospective,
mg/kg IV infused
participant resulted in unblinding
Peters A, Dryer J, et al. The relative efficacy of
Epsilon-
randomized, double-
over 15 min
(placebo group). In four
antifibrinolytics in adolescent idiopathic
Aminocaproic
blind comparison of
Maintenance
partipants, a drain was not
scoliosis: a prospective randomized trial. The
Acid,
tranexamic acid,
Dose= 1 mg/kg/hr
placed during the skin closure
Journal of bone and joint surgery American
Placebo (NS)
epsilon-aminocaproic
IV
due to unfamiliarity with protocol
volume. 2014 May 21;96(10):e80. Epub
acid, and placebo
and they were excluded from
2014/05/31.
used intraoperatively
drain output analysis. One
in patients with
participant was readmitted for
adolescent idiopathic
persistent wound drainage that
scoliosis in 125 pt. (36
resolved with antibiotic treatment.
TXA, 42
There were no renal,
Aminocaproic acid, 47
thromboembolic or other major
NS Placebo
complications observed in study.
Tranexamic
NCT01813058
Loading Dose=50
No patient in either group had
1.) Goobie SM, Meier PM, Sethna NF, et al.
Acid,
Efficacy of IV
mg/kg IV infused
clinical evidence of
Population pharmacokinetics of tranexamic acid
Placebo (NS)
Tranexamic Acid in
over 15 min
thromboembolic or neurologic
in paediatric patients undergoing
decreasing blood loss
Maintenance
complications. Analysis
craniosynostosis surgery. Clinical
in pediatric idiopathic
Dose= 10
confirmed that the PK of TXA in
pharmacokinetics 2013; 52:267-76.
scoliosis surgery?
mg/kg/hr IV during
craniosynostosis paediatric
2. )Goobie SM, Meier PM, Pereira LM,
surgery or
surgical patients is well described
McGowan FX, Prescilla RP, Scharp LA, Rogers
Placebo (NS)
by a structural two-
GF, Proctor MR, Meara JG, Soriano SG,
compartmental open model.
Zurakowski D, Sethna NF. Efficacy of
Incorporating bodyweight and
tranexamic acid in pediatric craniosynostosis
age significantly influenced
surgery: a double-blind, placebo-controlled trial.
individual pharmacokinetic
Anesthesiology. 2011 Apr;114(4):862-71.
parameters and improved TXA
3.) Sethna NF, Zurakowski D, Brustowicz RM,
predicted concentrations. Of
Bacsik J, Sullivan LJ, Shapiro F. Tranexamic
particular clinical significance, CL
acid reduces intraoperative blood loss in
was determined to be related to
pediatric patients undergoing scoliosis surgery.
bodyweight and age. Patients
Anesthesiology. 2005 Apr;102(4):727-32.
weighing ≤10 kg or age ≤12
months have significantly lower
CL than the others.
Tranexamic
NCT02840097
Loading Dose =
Acid,
Prospective, Phase 2,
15 mg/kg over 10
Placebo (NS)
Randomized, Triple
min followed by 2
Blind, Parallel
mg/kg/hr over 8
Assignment in
hrs
-
pediatric trauma (n=
or-
40 < 18 years)
Loading Dose =
30 mg/kg over 10
min followed by 4
mg/kg/h over 8
hrs or- Placebo
(NS)
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APPENDIX II IND DETERMINATION TABLE 3/3
Agent
FDA
Indication
Pediatric 
Indications
Pediatric Trials
Pediatric Dosing
FDA
Label 
Dose
Additional Safety Info
Reference
(clinicaltrials.gov)
Tranexamic 
Acid, 
Placebo 
(NS)
NCT02180321 Prospective, 
Randomized, Triple Blind, 
Parallel Assignment in pediatric 
patients undergoing 
craniosynostosis surgery (n=50 <
6 yrs)
Loading Dose=10 mg/kg IV infused 
over 15 min Maintenance Dose= 5 
mg/kg/hr IV of Placebo (NS)
Tranexamic 
Acid, 
Placebo 
(NS)
NCT00994994 Prospective, 
randomized parallel assigned 
single-blind study to determine if 
tranexamic acid reduces blood 
loss in pediatric cardiac surgery 
(n=160 2 mo to 18 years)
Loading Dose =50 mg/kg IV of 
tranexamic acid was given as a bolus 
at the induction of anesthesia, 
followed by 15 mg/kg of continuous 
infusion and another 50 mg/kg into the 
bypass circuit in TXA group. same 
volume of normal saline was given in 
Placebo group
One patient in the TXA group 
suffered from cerebral 
infarction at ~ 2 weeks post- 
surgery. The neurological 
status gradually improved on 
an outpatient clinic basis.
There were no significant 
differences in pre- and postop 
creatinine values between the 
TXA and placebo groups.
Shimizu K, Toda Y, 
Iwasaki T, Takeuchi M, 
Morimatsu H, Egi M, 
Suemori T, Suzuki S, 
Morita K, Sano S. Effect 
of tranexamic acid on 
blood loss in pediatric 
cardiac surgery: a 
randomized trial. J 
Anesth. 2011 
Dec;25(6):823-30. doi: 
10.1007/s00540-011-
1235-z. Epub 2011 Sep 
24.
Tranexamic 
Acid or No 
Intervention
NCT03128866
Prospective, 
randomized parallel assignment 
open label study reducing blood 
loss in hemipelvectomy surgery 
with use tranexamic acid
1. Adult patients and pediatric patients
> 40 kg given a loading dose of 15 
mg/kg 30 min prior to skin incision 
over 15 minutes followed by a 10 
mg/kg/hour maintenance infusion 
during the surgical procedure. TXA 
infusion discontinued after wound 
closure.
2. Pediatric patients 
(age < 12 and weight 5 - 40 kg) given 
a loading dose of 6.4 mg/kg 
(maximum 1 gram) dose 30 minutes 
prior to skin incision over 15 minutes, 
followed by 2 - 3.1 mg/kg/hr 
maintenance infusion until skin closure
Tranexamic 
Acid, 
Placebo 
(NS)
NCT03714360
Prospective, 
Phase 4 randomized double-blind 
placebo-controlled, parallel-group 
study of tranexamic acid during 
minor lumbar spinal surgery (ASA 
grades 1 or 2) (n=250 pediatric 
and adult)
Single dose of 10mg/kg IV (max= 1 g) 
of TXA or equivalent volume of NS 
(placebo) prior to incision
No safety listed in 
clinicaltrials.gov, but brief 
summary stated mean 
postoperative blood loss in 
patients who received 
tranexamic acid was 
statistically significantly lower 
than placebo.
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APPENDIX III: TESTS PERFORMED FOR GOOD CLINICAL CARE
All tests and evaluations mentioned in the protocol are considered Standard of Care except for those listed in 
APPENDIX IV.
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APPENDIX IV: RESEARCH TESTS
Research Test
Pre-Study
During Study
End of Study
ROTEM
No
In PACU,
required
No
Tranexamic 
acid (TXA)
No
1 IV dose over 
5 to 15 
minutes; 
second IV 
dose over 5 to 
15 minutes to
be given 6 
hours later if 
serum 
creatinine 
level has not 
doubled
No
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APPENDIX V: FUNCTIONAL ASSESSMENT
Functional Mobility Assessment (FMA) is a tool that was developed to measure functional mobility in children and adolescents 
with lower-extremity sarcoma. It is comprised of well-established outcome measures that examine various domains of function. 
The six categories tested by the FMA include pain, functional mobility, use of assistive devices, satisfaction with quality of gait, 
participation in the community, and endurance. 1.) Pain is measured by using a numeric scale requiring patients to rate any pain 
experienced in the prior week on a 0 (no pain) to 10 (worst pain imaginable) scale. 2.) Functional mobility will be measured by 
using the Timed Up and Down Stairs (TUDS) and Timed Up and Go (TUG). TUDS assesses the time required for a patient to 
walk up and down 12 stairs to measure functional mobility, balance, and motor skills. TUG measures the time needed to stand 
from a seated position, ambulate 3 meters, turn around, return to chair and resume sitting. This will provide a measure of dynamic 
balance and mobility. 3-5.) The use of supports, patient satisfaction, and participation in the community will be measured by 
patient provided responses to questions pertaining to the use of supports (brace, cane, crutches), satisfaction with walking quality, 
and participation in school, work, and/or sports. The responses will be scored on a 0-5 scale, with 0 demonstrating the least 
preferred outcome. 6.) A modification for the FMA will be implemented to measure endurance, which will be assessed using the 
9-Minute Run-Walk Test. The patient will be instructed to walk or run for 9 minutes while trying to cover as much distance as 
possible. Heart rate (HR) and rate of perceived exertion (RPE) data will be collected during the walk/run. RPE measures the level 
of the patient’s exertion using a likert scale of numbers (6-20) and adjectives describing effort. A wheeled feet counter will 
measure distance and a stopwatch will track time. Upon completion of the 9-minute run-walk, the physiological cost index (PCI) 
will be calculated by dividing the difference in the patient’s heart rate (HR while walking- HR at rest) by walking speed in meters 
per minute. Marchese, et al.20 reported that the FMA demonstrated good internal consistency as well as good construct validity in 
its ability to discriminate between patients with lower extremity malignancy and healthy controls.
-
Range of Motion Active and passive ROM will be measured using a goniometer. Measurements for patients with lower 
extremity surgery will include hip flexion, hip abduction and adduction, hip internal and external rotation, knee flexion and 
extension, and ankle dorsiflexion. ROM will be attempted on bilateral lower extremities, however if post-operative ROM 
precautions are implemented, the involved extremity will not be measured. Goniometry is a reliable and valid measure for 
active and passive ROM when following standardized procedures.
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Lower Extremity ROM
ROM Measure
Procedural 
Description
Patient 
Position
Pivot Point
Stationary 
Arm
Moving Arm
Hip flexion
The contralateral 
LE stabilized with 
hip and knee 
flexed
Supine
Greater 
Trochanter
Parallel to the 
long axis of 
the trunk and 
spine
Parallel to long axis of femur
Hip abduction and 
adduction
Stabilize the 
contralateral LE
Supine
Anterior 
superior iliac 
spine
Anterior 
superior iliac 
spine
Parallel to long axis of femur
Hip internal and 
external rotation
Stabilize the 
contralateral LE
Sitting
Tibial 
tuberosity
Parallel to 
floor
Parallel to tibial crest
Knee Flexion and 
Extension
Stabilize the 
contralateral LE
Supine
Lateral 
femoral 
condyle
Parallel to the 
long axis of 
femur
Parallel to long axis of fibula
Ankle 
Dorsiflexion
Stabilize the 
contralateral LE
Sitting
Posterior and 
inferior to 
lateral 
malleolus
Parallel to 
long axis of 
fibula
Parallel to fifth metatarsal
Patient-Reported Outcomes Measurement Information System (PROMIS) is a patient-reported outcome tool created by the National 
Institutes of Health (NIH), to establish a means of systematic outcome reporting for all patients across the health care spectrum.21 Due to its 
efficiency, reliability, and applicability to all patient types, the PROMIS continues to grow in popularity in many fields of medicine, including 
pediatrics, oncology, and orthopedics.22-25 It has shown good validity in both adult and pediatric populations, and is available in pediatric (ages 8- 
17), adult (ages 18 and older), and parent proxy (ages 5-17, or those unable to complete form independently) versions. The physical function 
domain of the PROMIS is intended to capture a patient’s self-reported ability to perform daily activities, self-care, and athletic activities, and are 
subdivided into the areas of mobility and upper extremity. Additional domains utilized for this study include strength impact and pain 
interference. PROMIS forms will be provided to all patients enrolled on this study at the time of their functional assessment with adequate, 
allotted time for completion of questionnaires, and collection of forms at the end of assessment appointment.
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APPENDIX VI: RELATION OF STUDY ENDPOINTS TO PROTOCOL OBJECTIVES
Item
Pre-OP
PACU
1-6 d Post- 
OP
1 wk. 
Post- 
OP
2 wks. 
Post- 
OP
4 wks. 
Post- 
OP
6 wks. 
Post- 
OP
2
mos. 
Post-OP
3 mos. 
Post-OP
6 mos. 
Post-OP
Objectives 1.1.1 & 1.2.3 & 1.3.2: 
Amount of Blood transfused/ placebo arm
X
X
Objectives 1.1.1 & 1.2.3 & 1.3.2:
Amount of Blood transfused/ TXA- treatment 
arm
X
X
Objectives 1.2.1:
Platelet changes/placebo arm
X
X
X
X
Objective 1.2.1:
Platelet changes/TXA-treatment arm
X
X
X
X
Objective 1.2.1:
Hemoglobin changes/ placebo arm
X
X
X
X
Objective 1.2.1:
Hemoglobin changes/ TXA-treatment arm
X
X
X
X
Objective 1.2.2:
Drain output/placebo arm
X
X
X
Objective 1.2.2:
Drain output/ TXA-treatment arm
X
X
X
Objectives 1.2.3 & 1.2.4 & 1.3.2: 
EBL/placebo arm (includes sponge counts + 
other measures during surgery)
X
Objectives 1.2.3 & 1.2.4 & 1.3.2: 
EBL/TXA treatment arm (includes sponge 
counts + other measures during surgery)
X
Physical Therapy Attendance (could relate to 
obj 1.3.1)
X
X
X
X
X
X
X
X
X
Objective 1.3.1: FMA
X
X
X
Objective 1.3.1: PROMIS
X
X
X
X
Objective 1.3.2 ROTEM
X
Objective 1.3.3 Wound f/u placebo arm (as 
needed)
X
X
X
X
X
X
X
X
X
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Objective 1.3.3 Wound f/u TXA-treatment 
arm (as needed)
X
X
X
X
X
X
X
X
X
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