Clinical trial NCT03425799
Conditions: Spinal Fusion
Sponsor: Exela Pharma Sciences, LLC.
Start date: 2018-10-17; Completion date: 2020-01-21
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to see if Tranexamic Acid can safely reduce bleeding in people undergoing spinal fusion surgery.

Detailed description:
This will be a multicenter, randomized, double-blind, parallel group study comparing tranexamic acid (test) to placebo (control) for reduction of perioperative blood loss after complex spinal fusion surgery (defined as T2 to Pelvis/Sacrum and greater than 4 Functional Spinal Units (4 discs/motion segments=5 Vertebral segments)). In addition to test and control treatments, all patients undergoing spinal fusion surgery will receive anesthesia and standard of care for blood loss including colloid/crystalloid fluid replacement and packed red cells, if necessary, according to a common multi-institutional protocol. Anesthesia will keep the mean arterial pressure as low as safe for the patient during exposure of surgery (estimated at 60-80 MAP). Patients will be randomized to receive either 30 mg/kg tranexamic acid as a one hour infusion (3 mL/kg) loading dose prior to start of procedure and as an infusion at 3 mg/kg/h (0.3 mL/kg/h) of tranexamic acid throughout the surgery in the test group; or, a one hour infusion at 3 mL/kg of 0.9% saline prior to start of the procedure and an infusion of 0.9% saline at 0.3 mL/kg/h in the control group. The maximum total dose will be 50 mg/kg.

The active phase of the study will be until discharge postoperatively for efficacy measurements and at 6 weeks for safety follow-up. The randomization will be open only to the statistician generating the randomization sequence. All PI(s), study conduct and monitoring staff, as well as the subjects will be completely blinded to the treatments except in the case of emergency.

The study will be terminated if ≥5/12 or 10/36 patients enrolled in the study are diagnosed with treatment related serious adverse events.

Arms: arm 1: Sodium Chloride 0.9% infused at 3 mL/kg over one hour followed by continuous infusion at 0.3 mL/kg for maximum infusion volume of 5 mL/kg arm 2: Tranexamic Acid 10 mg/mL infused at 3 mL/kg over one hour followed by continuous infusion at 0.3 mL/kg for maximum infusion volume of 5 mL/kg
Interventions: intervention 1: Sodium Chloride 0.9% Inj intervention 2: Tranexamic Acid
Intervention descriptions: intervention 1: Inactive ingredient mixture for injection without drug, intravenous infusion bags containing normal saline, manufactured and provided by Exela Pharma Sciences, LLC from a single batch / lot. intervention 2: Tranexamic Acid Intravenous Infusion Bags (10 mg/mL), manufactured and provided by Exela Pharma Sciences, LLC from a single batch / lot.

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
 
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CLINICAL STUDY PROTOCOL 
EFFICACY AND SAFETY OF TRANEXAMIC ACID IN SPINAL 
FUSION SURGERY 
Principal Investigator 
Neel Anand, M.D. 
Principal Investigator 
Sig Berven, M.D. 
Principal Investigator 
Aaron Buckland, M.D. 
Principal Investigator 
Stuart H. Hershman, M.D., FAAOS 
Principal Investigator 
Philip Yuan, M.D. 
Principal Investigator 
Brian Hsu, M.D. 
Principal Investigator 
Arvind Dubey, M.D 
Principal Investigator 
Christopher DeWald, M.D. 
Sponsor 
Exela Pharma Sciences, LLC 
1245 Blowing Rock Blvd. 
PO box 818 Lenoir, NC 28645 
Sponsor Contact 
Jason Liu, PharmD  
Email:  jliu@exela.us  
Tel: 828-758-5474 ext 196 (Office)    
 
CRO Contact 
Marcy T. Rogers 
SpineMark Corporation 
6020 Cornerstone Court West Ste 230 
San Diego, CA92121 
Email:  mrogers@spinemark.com  
Tel: 858-335-8254 (Cell) 
Approval Date 
May 29, 2018 
Version 
v.1.6 
 
 
 
Confidentiality Statement 
Any and all information presented in this document shall be treated as confidential. This document was 
developed by Exela Pharma Sciences and should not be disclosed, published or otherwise communicated to a 
third party, with the exception of appropriate institutional review boards/ethical committees, unless required by  
federal or state law or regulation, without prior written consent of the Sponsor or authorized representatives.  


 
 
 
 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS ............................................................................ 6 
2. 
STATEMENT OF COMPLIANCE .................................................................. 8 
3. 
PROTOCOL SYNOPSIS ................................................................................... 9 
4. 
SCHEDULE OF PROCEDURES ................................................................... 19 
5. 
SCHEMATIC OF STUDY DESIGN .............................................................. 21 
6. 
BACKGROUND INFORMATION ................................................................ 22 
6.1. 
Background and Literature ...................................................................... 22 
6.2. 
Rationale ..................................................................................................... 23 
6.3. 
Potential Risks and Benefits ...................................................................... 24 
6.3.1. 
Known Potential Risks2 ...................................................................... 24 
6.3.2. 
Known Potential Benefits ................................................................... 25 
7. 
TRIAL OBJECTIVES AND PURPOSE ........................................................ 26 
8. 
TRIAL DESIGN................................................................................................ 27 
8.1. 
Description of Study Design ...................................................................... 27 
8.2. 
Study Endpoints ......................................................................................... 27 
8.2.1. 
Primary Endpoints.............................................................................. 27 
8.2.2. 
Secondary Endpoints .......................................................................... 28 
8.3. 
Study Population ........................................................................................ 28 
8.3.1. 
Inclusion Criteria ................................................................................ 29 
8.3.2. 
Exclusion Criteria ............................................................................... 29 
8.3.3. 
Withdrawal Criteria ........................................................................... 31 
8.4. 
Randomization and Blinding .................................................................... 31 
9. 
STUDY AGENT ................................................................................................ 33 
9.1. 
Study Agent(s) Administration ................................................................. 33 
9.1.1. 
Study Agent(s) Description ................................................................ 33 
9.1.2. 
Dosing and Administration ................................................................ 33 
9.1.3. 
Formulation, Appearance, Packaging, and Labeling ...................... 33 
9.2. 
Preparation/Handling/Storage/Accountability ........................................ 33 


 
 
 
 
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9.2.1. 
Acquisition and Accountability ......................................................... 33 
9.2.2. 
Product Storage and Stability ............................................................ 34 
9.2.3. 
Preparation .......................................................................................... 34 
9.2.4. 
Retention Samples ............................................................................... 34 
10. 
STUDY PROCEDURES AND SCHEDULE ............................................... 35 
10.1. 
Study Procedures/Evaluations............................................................... 35 
10.1.1. 
Study Specific Procedures .............................................................. 35 
10.2. 
Laboratory Procedures/Evaluations ..................................................... 35 
10.2.1. 
Clinical Laboratory Evaluations ................................................... 35 
10.2.2. 
Other Assays or Procedures ........................................................... 36 
10.2.3. 
Specimen Preparation, Handling, and Storage ............................ 36 
10.2.4. 
Specimen Shipment ......................................................................... 36 
10.3. 
Study Schedule ........................................................................................ 36 
10.3.1. 
Screening .......................................................................................... 36 
10.3.2. 
Pre-Treatment Procedures ............................................................. 37 
10.3.3. 
Drug Dosing ..................................................................................... 37 
10.3.4. 
Follow-Up Procedures..................................................................... 38 
10.3.5. 
Final Study/Early Termination Visit ............................................. 39 
10.4. 
Concomitant Medications, Treatments, and Procedures.................... 40 
10.5. 
Efficacy Assessments .............................................................................. 40 
10.6. 
Safety and Other Assessments ............................................................... 41 
10.7. 
Adverse Events and Serious Adverse Events ....................................... 42 
10.7.1. 
Definitions ........................................................................................ 42 
10.7.2. 
Classification of an Adverse Event ................................................ 43 
10.7.3. 
Adverse Event and Pregnancy Follow-Up .................................... 46 
10.7.4. 
Adverse Event Reporting ............................................................... 46 
10.7.5. 
Serious Adverse Event Reporting .................................................. 47 
11. 
STATISTICAL CONSIDERATIONS ......................................................... 48 
11.1. 
Statistical Hypothesis ............................................................................. 48 
11.2. 
Sample Size Determination .................................................................... 48 


 
 
 
 
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11.3. 
Populations for Analysis ........................................................................ 48 
11.4. 
Statistical Analysis .................................................................................. 49 
11.4.1. 
General Approach ........................................................................... 49 
11.4.2. 
Analysis of Primary Efficacy Endpoint(s) .................................... 49 
11.4.3. 
Analysis of Secondary Efficacy Endpoint(s) ................................. 50 
11.4.4. 
Safety Analysis ................................................................................. 50 
11.4.5. 
Baseline Descriptive Statistics ........................................................ 50 
11.4.6. 
Planned Interim Analysis ............................................................... 50 
11.4.7. 
Sub-Group Analysis ........................................................................ 51 
11.4.8. 
Tabulation of Individual Participant Data ................................... 51 
11.4.9. 
Exploratory Analysis....................................................................... 51 
12. 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS ................................................................................................ 52 
12.1. 
Informed Consent Process ..................................................................... 52 
12.2. 
Confidentiality and Privacy ................................................................... 52 
12.3. 
Key Roles and Study Governance ......................................................... 52 
12.4. 
Safety Oversight ...................................................................................... 53 
12.5. 
Clinical Monitoring ................................................................................ 53 
12.6. 
Quality Assurance and Quality Control ............................................... 53 
12.7. 
Data Handling and Record Keeping ..................................................... 54 
12.7.1. 
Data Collection and Management Responsibilities ...................... 54 
12.7.2. 
Study Records and Retention Samples.......................................... 54 
12.8. 
Protocol Deviations ................................................................................. 54 
12.9. 
Publication and Sharing Policy ............................................................. 54 
12.10. 
Final Report ............................................................................................ 55 
13. 
PROTOCOL AMENDMENT HISTORY ................................................... 56 
14. 
REFERENCES ............................................................................................... 58 
15. 
PRINCIPAL INVESTIGATOR’S STATEMENT AND SPONSOR 
APPROVAL SIGNATURE...................................................................................... 60 
16. 
APPENDIX ..................................................................................................... 62 


 
 
 
 
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1. LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ANOVA 
Analysis of variance 
ATC 
Anatomical Therapeutic Class 
BQL 
Below limit of quantitation 
BUN 
Blood urea nitrogen 
CI 
Confidence Interval 
Cmax 
Maximum serum concentration 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
DVT 
Deep vein thrombosis 
EBV 
Estimated blood volume 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FFP 
Fresh frozen plasma 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
Hct0 
Hematocrit at -1 h before surgery 
Hctf 
Hematocrit at 48 h after wound closure 
Hctav 
Hematocrit average 
HCV 
Hepatitis C virus 
IC 
Informed consent 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
MI 
Myocardial infarction 
mL 
Milliliter(s) 
OTC 
Over-the-counter 
PK 
Pharmacokinetic(s) 
R 
Reference formulation 
T 
Test formulation 


 
 
 
 
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RLD 
Reference Listed Drug 
RBC 
Red blood cell 
WBC 
White blood cell 
SAE 
Serious adverse event 
TEAE 
Treatment-emergent adverse events 
VL 
Volume of blood loss 
 
 


 
 
 
 
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2. STATEMENT OF COMPLIANCE 
The study will be conducted in compliance with applicable FDA and ICH rules, 
regulations, and guidelines and applicable laws and regulations of the locale and 
country where the study is conducted. The study will be conducted with the 
approval of a duly constituted institutional review board (IRB) or ethics 
committee (EC) in accordance with the requirement of 21 CFR 56 - Institutional 
Review Boards. The nature and risks of the study will be fully explained to each 
subject and written consent, obtained in accordance with the requirements of 21 
CFR 50 and 45 CFR 46 - Protection of Human Subjects. Subjects will be 
informed of their rights, including the right to withdraw from the study at any 
time. 
The Principal Investigator(s) will assure that no deviation from, or changes to the 
protocol will take place without prior agreement from the sponsor and 
documented approval from the Institutional Review Board (IRB), except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All 
personnel involved in the conduct of this study have completed Human Subjects 
Protection Training. 
I agree to ensure that all staff members involved in the conduct of this study are 
informed about their obligations in meeting the above commitments. 
 
 
PI Name 
 
Date 
Title 
 
 
Organization 
 
 
 
 
 


 
 
 
 
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3. PROTOCOL SYNOPSIS 
Protocol Number 
and Title: 
 
CP-006-2017 – Efficacy and safety of tranexamic acid 
in spinal fusion surgery 
Study 
Objectives: 
 
The primary objectives of this trial are to assess: 
1. Total Blood Loss based on changes in 
hemoglobin (Blood loss will be calculated by 
Nadler’s and Gross’s formulae from the time of 
admission to hospital until discharge; 
Hemoglobin and hematocrit concentrations will 
be measured pre-operatively, post-operatively, 
and at 24 h and every 24h thereafter until 
discharge). 
2. Incidence of autologous or allogenic blood 
transfusion, including red blood cells and 
coagulation components (such as fresh frozen 
plasma and platelets). 
Secondary objectives include assessment of: 
1. Total measured blood loss (measured intra-
operatively and for up to 24 hours post-
operatively and every 24 hours up to discharge 
when the two subfascial drains are removed). 
Total Blood Loss may be estimated as 3 times 
cell saver. 
2. Number of patients with symptomatic anemia 
(such as tachycardia, hypotension, presyncope) 
of <8.0 g/dL hemoglobin, or any hemoglobin 
<7.0 g/dL, precipitated transfusion. 
[Alternatively, allogenic blood transfusion will 
be considered for hemoglobin <9 g/dL 
intraoperatively or <8 g/dL post-operatively] 
3. Number of patients with adverse events related 
to tranexamic acid such as confirmed deep vein 
thrombosis (DVT), pulmonary embolism (PE), 
or seizures. 
4. Other outcomes will include functional 
recovery, duration of hospital stay, and wound 


 
 
 
 
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complications (infections, hematomas, and other 
complications related with surgery). 
 
Number of Sites: 
 
8 
Principal 
Investigator and 
Study Site 1: 
 
Neel Anand, M.D. 
Clinical Professor of Surgery 
Cedars -Sinai Medical Center 
444 South San Vincente Boulevard, Ste 901 
Los Angeles, CA 90048 
 
Principal 
Investigator and 
Study Site 2: 
 
Sig Berven, M.D. 
UCSF Spine Center 
400 Parnassus Avenue, Third Floor 
San Francisco, CA  94143 
 
Principal 
Investigator and 
Study Site 3: 
 
Aaron Buckland, M.D. 
Spine Care Orthopedics 
NYU Langone Medical Center 
333 E 38th St., NY, NY 
 
Principal 
Investigator and 
Study Site 4: 
 
Stuart H. Hershman, M.D. FAAOS 
Massachusetts General Hospital 
Department of Orthopaedic Surgery 
55 Fruit St. Yawkey 3 
Boston MA 02114 
 
Principal 
Investigator and 
Study Site 5: 
 
Philip Yuan, M.D.  
Memorial Orthopaedic Surgery Group 
2760 Atlantic Avenue 
Long Beach, CA  90806 
 
Principal 
Investigator and 
Study Site 6: 
 
 
Christopher DeWald, M.D. 
Matthew Colman, MD PIs, Frank Philips, M.D., Sub PI 
Division of Spine Surgery 
Rush University Medical Center 
Chicago IL 
 


 
 
 
 
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Principal 
Investigator and 
Study Site 7: 
 
Arvind Dubey, M.D. 
438 Elizabeth St, Hobart TAS 7000, Australia 
Hobart, Tasmania 
 
Principal 
Investigator and 
Study Site 8: 
 
Brian Hsu, M.D.  
2/445 Victoria Ave, Chatswood NSW 2067, Australia 
Sydney, NSW  
Clinical 
Laboratory: 
 
 
Institutional 
Review Board: 
 
Western Institutional Review Board  
Research Foundation 
Address: 1019 39th Ave SE #120, Puyallup, WA 98374 
Phone:(360) 252-2500 
Test and 
Reference 
Products: 
 
Test Drug: Exela’s Tranexamic Acid Solution for 
Injection (10 mg/mL), intravenous infusion bags, 
manufactured and provided by Exela Pharma Sciences, 
LLC from a single batch / lot will be administered to all 
randomized subjects. 
Placebo: Inactive ingredient mixture for injection 
without drug, intravenous infusion bags containing 
normal saline, manufactured and provided by Exela 
Pharma Sciences, LLC from a single batch / lot will be 
administered to all randomized subjects. 
Study Design 
and Duration of 
Treatment: 
 
 
 
 
 
This will be a multicenter, randomized, double-blind, 
parallel group study comparing tranexamic acid (test) to 
placebo (control) for reduction of perioperative blood 
loss after complex spinal fusion surgery (defined as T2 
to Pelvis/Sacrum and greater than 4 Functional Spinal 
Units (4 discs/motion segments=5 Vertebral segments)). 
In addition to test and control treatments, all patients 
undergoing spinal fusion surgery will receive anesthesia 
and standard of care for blood loss including 
colloid/crystalloid fluid replacement and packed red 


 
 
 
 
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Study 
Termination 
cells, if necessary, according to a common multi-
institutional protocol. Anesthesia will keep the mean 
arterial pressure as low as safe for the patient during 
exposure of surgery (estimated at 60-80 MAP). Patients 
will be randomized to receive either 30 mg/kg 
tranexamic acid as a one hour infusion (3 mL/kg) 
loading dose prior to start of procedure and as an 
infusion at 3 mg/kg/h (0.3 mL/kg/h) of tranexamic acid 
throughout the surgery in the test group; or, a one hour 
infusion at 3 mL/kg of 0.9% saline prior to start of the 
procedure and an infusion of 0.9% saline at 0.3 mL/kg/h 
in the control group. The maximum total dose will be 
50 mg/kg. 
The active phase of the study will be until discharge 
postoperatively for efficacy measurements and at 6 
weeks for safety follow-up. The randomization will be 
open only to the statistician generating the 
randomization sequence. All PI(s), study conduct and 
monitoring staff, as well as the subjects will be 
completely blinded to the treatments except in the case 
of emergency. 
The study will be terminated if ≥5/12 or 10/36 patients 
enrolled in the study are diagnosed with treatment 
related serious adverse events. 
Phase: 
 
This will be a Phase III study. 
Inclusion 
Criteria: 
 
All adult patients over age eighteen electively 
undergoing complex spinal fusion surgery (T2 to 
Pelvis/Sacrum, greater than 4 FSU’s (5 vertebral 
segments or more)) and have a negative serum 
pregnancy test result at screening, if female, will be 
eligible.  


 
 
 
 
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Exclusion 
Criteria: 
 
Allergy to tranexamic acid; spinal tumor/intradural 
pathology; ankylosing spondylitis; acquired disturbance 
of color vision; pre-operative anemia (Hb <110 in 
females, Hb <120 in males); refusal of blood products 
(Jehova’s witnesses); pre-operative use of anticoagulant 
therapy (Coumadin or heparin within 5 days of 
surgery); fibrinolytic disorders requiring intra-operative 
antifibrinolytic treatment; hematological disease 
(thromboembolic events, hemoglobinopathy, 
coagulopathy, or hemolytic disease); female patients 
using combination hormonal contraception; patients 
with history of subarachnoid hemorrhage; patients with 
serum creatinine levels above ULN 
Population: 
 
Up to approximately 150 patients will be enrolled.   
Study Duration: 
 
Approximately 2 months, including a screening visit, 
drug dosing during surgery, and a 6 week follow up.   
Study 
Procedures: 
 
Subjects who meet admission criteria will be assigned 
sequential numbers beginning with site#-001.  A 
completed subject is a subject who satisfies the 
admission criteria and who completes all required 
assessments.  When the subjects meet admission criteria 
and provide written informed consent, they will receive 
a subject number and be randomized by subject number 
into one of two treatment arms. They will receive either 
tranexamic acid or normal saline according to the 
randomization schedule. 
Preoperative Visit: Subjects will provide written 
informed consent and will then undergo pre-operative 
data collection/screening, including: 
• Inclusion Exclusion criteria assessment 
• Diagnosis leading to surgery 
• Planned procedure 


 
 
 
 
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• Schwab Curve type and coronal curve 
magnitude (Cobb angle) 
• Patient age and demography 
• Height, Weight, and Body Mass Index 
• Number of units of autologous blood donation 
• CBC: Hb/Hct/WBC/platelet count (post-
autologous donation) 
• Coagulation Profile: PT/PTT/INR 
• Medical History and Medication Use 
• History of Previous Spine Surgery 
• Drug / Alcohol / Tobacco Use 
• Medication Allergies 
• Pregnancy testing (females only) 
Surgery, Drug Dosing, and Hospital Stay: Blinded 
treatments will be administered at an initial dose of 
3 mL/kg as a 1-hour infusion using a calibrated infusion 
pump prior to start of procedure, and as a 0.3 mL/kg/h 
infusion throughout the surgery.  Blood lost during 
surgery will be collected by subfascial Hemovac drains 
at the incision site into canisters containing heparinized 
saline. Volumes collected will be recorded post-surgery 
and every 24 h thereafter until discharge. Measured 
Blood Loss will be estimated as 3 times cell saver; 
estimates will be taken off of the anesthesia record.  
The site will provide a person who will collect blood 
during consult in OR and record variables and 
measurements on the data collection sheet throughout 
the entire surgery.  Final Measured Blood Loss will be 
determined post removal of the two subfascial hemovac 
drains placed during the procedure.    


 
 
 
 
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The Total Blood Loss will be estimated based on the 
hemoglobin content of the blood prior to surgery 
(mg/dL) and at each of the desired post-surgery time-
points (mg/dL). Blood samples for hemoglobin 
measurement will be collected prior to start of 
procedure, at the end of the procedure, at 24 h, and 
every 24 h thereafter until discharge and removal two 
subfascial drains.  Hematocrit analysis will also be 
conducted on all collected blood samples. The total 
amounts of fluids infused and amounts of any red blood 
cell transfusions may be considered, as applicable, in 
determining the changes in hemoglobin. 
In addition, the following data will be recorded: 
• Treatment ID 
• Details of surgical procedure [Number of 
vertebrae fused, number of anchors used, and 
type of anchors used (screws, hooks, or 
anchors); Number and type of osteotomies 
performed] 
• Any complication prolonging the surgery time 
or increasing patient blood loss 
• Surgery time 
• Estimated blood loss peri-operatively (from 
drainages and absorbent/surgical pads) 
• Volume of cell saver delivered 
• Units of autologous transfusion and allogenic 
transfusion 
• Units of fresh frozen plasma and platelets 
administered 
• Volume of crystalloids/colloids given 


 
 
 
 
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• Urine output 
• Location of Hemovac drains and number of 
drains placed 
• Drain output recorded daily 
• Length of drain use (uniformly remove drains 
when output <120 mL/day) 
• Length of hospital stay 
• Complications of autologous or allogenic 
transfusion 
• Complications of tranexamic acid including 
renal, hepatic, thromboembolic, and brain/CNS 
• Functional recovery assessments will be 
completed prior to discharge 
• Any wound complications for the duration of 
hospitalization 
 
Follow-up Procedures: Follow-ups on wound 
complications will be completed minimally at 6 weeks 
after surgery. Follow-ups on adverse events related to 
tranexamic acid (such as seizures, DVTs, and PEs) will 
be reported immediately if they occur. 
Adverse events (AEs) will also be monitored by the 
investigator and/or designated research staff and 
spontaneous reporting throughout the study.  
Confinement: 
 
Patients will be confined to the clinic for surgical 
procedures and recovery as directed by the principal 
investigator 
Study Endpoints:  
The primary endpoints of this trial are to assess: 


 
 
 
 
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1. Total Blood Loss based on changes in 
hemoglobin (Blood loss will be calculated by 
Nadler’s and Gross’s formulae from the time of 
admission to hospital until discharge; 
Hemoglobin and hematocrit concentrations will 
be measured pre-operatively, post-operatively, 
and at 24 h and every 24h thereafter until 
discharge). 
2. Incidence of autologous or allogenic blood 
transfusion, including red blood cells and 
coagulation components (such as fresh frozen 
plasma and platelets). 
 
 
The Secondary endpoints include assessment of: 
 
1. Total Measured Blood Loss (measured intra-
operatively and for up to 24 hours post-
operatively and every 24 hours up to discharge 
when the two subfascial drains are removed). 
Total Measured Blood Loss will be estimated as 
3 times cell saver. 
 
2. Number of patients with symptomatic anemia 
(such as tachycardia, hypotension, presyncope) 
of <8.0 g/dL hemoglobin, or any hemoglobin 
<7.0 g/dL, precipitated transfusion. 
[Alternatively, allogenic blood transfusion will 
be considered for hemoglobin <9 g/dL 
intraoperatively or <8 g/dL post-operatively] 
 
3. Number of patients with adverse events related 
to tranexamic acid such as confirmed deep vein 
thrombosis (DVT), pulmonary embolism (PE), 
or seizures. 
 
4. Other outcomes will include functional 
recovery, duration of hospital stay, and wound 


 
 
 
 
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complications (infections, hematomas, and other 
complications related with surgery). 
Safety 
Assessments: 
 
Safety assessments will include monitoring of AEs, and 
functional recovery assessments, wound complications, 
length of hospital stay, blood loss, and transfusions. 
Statistical 
Methods: 
 
The primary efficacy variables and continuous 
secondary efficacy variables will be analysed using 
Analysis of Covariance (ANCOVA) where one factor is 
treatment (TXA vs Placebo) and the other factor is 
Surgeon.  The initial analysis will include the 
interaction between the two factors in order to assess the 
similarity of effects across surgeons.  Significant 
interaction effects will occur if (for example), TXA 
works for some surgeons but not for others.  The final 
efficacy analysis will remove the interaction term and 
control for overall differences between surgeons.  
Adverse events will be categorized using MedDRA 
codes. The TXA and placebo groups will be compared 
using Fisher exact tests of the number of patients with 
each category of adverse events.  The total number of 
reported adverse events will also be presented. 
 
 


 
 
 
 
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4. SCHEDULE OF PROCEDURES 
Evaluation 
Procedure 
Screening 
Visit 
 
Day of 
Surgery 
Discharge 
Safety Follow-ups  
Study Exit 
or Early 
Withdrawal8 
 
 
24 h 
Every 
24 h until 
discharge 
6 
weeks 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Diagnosis leading to 
surgery 
X 
 
 
 
 
 
 
Planned procedure 
X 
 
 
 
 
 
 
Schwab Curve type 
and coronal curve 
magnitude (Cobb 
angle) 
X 
 
 
 
 
 
 
Patient age and 
demography 
X 
 
 
 
 
 
 
Medical/Medication 
Use History 
X 
 
 
 
 
 
 
History of previous 
spine surgery 
X 
 
 
 
 
 
 
Height, Weight, 
Body Mass Index  
X 
 
 
 
 
 
 
Number of units of 
autologous blood 
donation 
X 
 
 
 
 
 
 
CBC: 
Hb/Hct/WBC/platelet 
count (post-
autologous blood 
donation) 
X 
 
 
 
 
 
 
Coagulation Profile: 
PT/PTT/INR 
X 
 
 
 
 
 
 
Pregnancy Tests1 
X 
X 
 
 
 
 
 
Serum Creatinine 
X 
 
 
 
 
 
 
Drug / Alcohol 
/Tobacco Use 
X 
 
 
 
 
 
 
Medication Allergies 
X 
 
 
 
 
 
 
Physical 
Examination 
X 
X 
 
 
 
 
X 
Treatment ID 
 
X 
 
 
 
 
 
Details of surgical 
procedure2 
 
X 
 
 
 
 
 
Surgical 
complications 
 
X 
 
 
 
 
 
Surgery time 
 
X 
 
 
 
 
 
Volume of cell saver 
delivered 
 
X 
 
 
 
 
 


 
 
 
 
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Blood Collection3 
 
X 
X 
 
 
 
 
Location of Hemovac 
drains 
 
X 
 
 
 
 
 
Length of drain use 
 
 
X 
 
 
 
 
Length of hospital 
stay 
 
 
X 
 
 
 
 
Peri-operative Blood 
Loss Assessments4 
 
X 
X 
 
 
 
 
Transfusions5 
 
X 
 
 
 
 
 
Complications 
related to 
transfusions 
 
X 
X 
 
 
 
 
Urine output6 
 
X 
 
 
 
 
 
Tranexamic acid 
related 
complications7 
 
X 
X 
X 
X 
X 
X 
Functional recovery 
assessment 
 
X 
X 
X 
X 
X 
X 
Wound 
Complications 
 
X 
X 
X 
X 
X 
X 
 
1 Females must have a negative serum pregnancy test result at screening and a negative urine test prior to surgery. 
2Number of vertebrae fused, number of anchors used, and type of anchors used (screws, hooks, or anchors); 
Number and type of osteotomies performed 
3 Blood for Hb and Hct measurements will be collected pre-surgery, immediately post-surgery, at 24 h and every 
24 thereafter until discharge.  
4 Blood lost during surgery will be collected by subfascial Hemovac drains at the incision site into canisters 
containing heparinized saline. Volumes collected will be recorded post-surgery and every 24 h thereafter until 
discharge. Total measured blood loss will be estimated as 3X cell saver; estimates will be taken off of the 
anesthesia record.  The site will provide a person who will collect blood during consult in the OR and record 
variables and measurements on the data collection sheet throughout the entire surgery.  Final blood loss will be 
measured post removal of the two subfascial hemovac drains placed during the procedure.    
The total blood loss will be estimated based on the hemoglobin content of the blood prior to surgery (mg/dL), and 
post-surgery (mg/dL). Blood samples for hemoglobin measurement will be collected prior to start of procedure, at 
the end of the procedure, at 24 h, and every 24 h thereafter until discharge and removal of the two subfascial 
drains.  Hematocrit analysis will also be conducted on all collected blood samples. The total amounts of fluids 
infused and amounts of any red blood cell transfusions will be considered, as applicable, in determining the 
changes in hemoglobin. 
5 Units of autologous transfusion and allogenic transfusion; Units of fresh frozen plasma and platelets 
administered; Volume of crystalloids/colloids given. 
6  Urine output during surgery. 
7 Symptoms of thromboembolic complications will be followed and recorded.  Either radiocontrast venography or 
pulmonary scintigraphy will be used to confirm deep vein thrombosis or pulmonary emboli. Any observed 
seizures during the hospital stay will also be recorded and reported. 
 
 


 
 
 
 
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5. SCHEMATIC OF STUDY DESIGN 
 
CP-006-2017 – Efficacy and safety of tranexamic acid in spinal fusion surgery 
 
❖ Study Cohort  - > Adult patients over age 18 electively undergoing 
complex spinal fusion surgery (T2 to pelvis/Sacrum, greater than 4 FSU’s 
(5 vertebral segments or more)). 
 
❖ Arm 1 - >  
Subjects receiving study drug (treat) (n = 100). 
❖ Arm 2 - >  
Subjects receiving placebo (control) (n = 50). 
 
❖ Sample size - > 
150 study subjects; randomized 2:1 Treat / Control 
 
❖ Intervention: 
Arm1 – Surgery plus study drug 
   
 
 
Arm 2 – Surgery with placebo 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


 
 
 
 
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6. BACKGROUND INFORMATION 
6.1. Background and Literature 
Tranexamic acid is a synthetic derivative of the amino acid lysine that 
inhibits fibrinolysis by competitively inhibiting plasminogen activation, and 
to a lesser extent, noncompetitively inhibiting plasmin.  Tranexamic acid 
binds to lysine binding sites on plasminogen and plasmin thereby blocking 
the action of lysine and preventing fibrin clot breakdown.  It is used to treat 
or prevent excessive blood loss during surgery and in various coagulopathies.  
Following intravenous administration, tranexamic acid has a half-life for the 
terminal elimination phase of about 2 hours. Urinary excretion is the main 
route of elimination via glomerular filtration.  Overall renal clearance is equal 
to plasma clearance of 110-116 mL/min, and more than 95% of the dose is 
excreted in the urine as unchanged drug.   
Recently, the intravenous administration of a 1-gram loading dose and 1-
gram 8-hour continuous infusion of tranexamic acid has been shown to 
reduce all-cause mortality and mortality due to blood loss from serious 
hemorrhagic trauma injuries1.  The CRASH-2 trial showed that 
administration of tranexamic acid to adult trauma patients with, or at risk of, 
significant hemorrhage within 8 hours of injury significantly reduced all-
cause mortality with no apparent increase in vascular occlusive events.  As a 
consequence of this trial, tranexamic acid has been incorporated into trauma 
treatment protocols worldwide.  Tranexamic acid was added to the WHO list 
of essential medicines following the CRASH-2 study. In addition, numerous 
studies report the benefits and safety of tranexamic acid in cardiac, 
gynecological, and orthopedic surgeries. Albeit off-label, tranexamic acid is 
part of the standard of care protocols of several orthopedic surgery centers for 
total knee-arthroplasty and hip replacement in the United States. 
In the United States, FDA approved indications for tranexamic acid, are 
limited.  It is indicated for treatment of patients with hemophilia to reduce or 
prevent hemorrhage and reduce the need for replacement therapy during and 
following tooth extraction, and for the treatment of menorrhagia in women. 


 
 
 
 
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The current dosage regimen for intravenous tranexamic acid is to administer 
10 mg/kg of CYKLOKAPRON intravenously immediately before tooth 
extraction in patients with hemophilia. Following tooth extraction, 
intravenous therapy, at a dose of 10 mg/kg, 3 to 4 times daily may be used for 
2 to 8 days.2  
Exela Pharma Sciences has developed Tranexamic Acid Premixed Injection 
10 mg/mL in 0.7% sodium chloride (1gram tranexamic acid/100 mL).  The 
pH of the product is 6.5 to 8.0 and the osmolality is approximately 285 
mOsmol/kg.  Exela is seeking FDA approval and registration for indications 
related to the reduction of perioperative blood loss. 
6.2. Rationale 
As stated earlier, the CRASH-2 study established the safety and efficacy of 
tranexamic acid use in reducing blood loss in trauma situations and numerous 
reported studies support the safety and efficacy of tranexamic acid use for 
reduction of blood loss (or transfusions) in cardiac, gynecologic, and 
orthopedic surgeries. In addition, several surgical centers within the United 
States use tranexamic acid as part of their standard protocol during total knee-
arthroplasty and hip replacement surgeries. However, this use of tranexamic 
acid is currently off-label. Exela intends to obtain approval for its tranexamic 
acid product for the indication of “reduction of perioperative blood loss”.  
 
 
Several literature reported studies have shown tranexamic acid to be effective 
in reducing perioperative blood loss in spinal fusion surgeries. 3-9 However, 
most of these studies showing efficacy of tranexamic acid in spinal surgery 
were conducted outside the United States and used varying dosing regimens. 
For example, one study reported by Shapiro F, et.al., conducted at Childrens 
Hospital Boston and Harvard Medical School used high doses of tranexamic 
acid (100 mg/kg administered over 15 min, followed by a 10 mg/kg infusion 
throughout the surgery).3 These authors reported that blood loss was reduced 
by 42% in the tranexamic acid treated group. A Canadian study by Wong J, 
et.al., reported a 25-30% reduction in blood loss using a 10 mg/kg initial dose 


 
 
 
 
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followed by a maintenance infusion of 1 mg/kg/h until skin closure. 4 Another 
study by Grant JA, et al., compared a tranexamic acid bolus dose of 10 mg/kg 
followed by a 1 mg/kg/h infusion with a bolus dose of 20 mg/kg followed by a 
10 mg/kg/h infusion in patients with idiopathic scoliosis and reported a 50% 
reduction in blood loss following the high dose.5 Verma K et al. reported a 
study plan to compare a low dose tranexamic acid regimen to a high dose 
tranexamic acid regimen for use in spinal fusion surgeries.6 A meta-analysis 
that consolidated the findings of 11 randomized controlled trials which 
investigated the use of TXA on surgical bleeding in spine surgery concluded 
that surgical bleeding and transfusion requirements are reduced using TXA 
and that there is no apparent association with increased incidence of 
pulmonary embolism, DVT, or MI.7  
 
In summary, substantial support for the use of intravenously infused 
tranexamic acid in the field of spinal surgery exists.8,9 Exela aims to use the 
currently approved dosing regimen of “10 mg/kg initial dose followed by 3-4 
doses of 10 mg/kg per day” as the basis for the dosing regimen to be used in 
this study. The maximum dose as per the currently approved dosing regimen 
is 50 mg/kg (10 mg/kg initial dose + 4 doses of 10 mg/kg per day). The 
maximum dose to be administered is maintained as 50 mg/kg per day in the 
current protocol. However, the dosing regimen is modified as “30 mg/kg over 
1-hour as an initial dose prior to surgery and an infusion dose of 3 mg/kg/h 
throughout the surgery up to a maximum of 50 mg/kg”. 
 
6.3. Potential Risks and Benefits 
6.3.1. Known Potential Risks2 
Visual abnormalities, often poorly characterized, represent the most 
frequently reported postmarketing adverse reaction in Sweden.  No 
retinal changes have been reported or noted in eye examinations in 
patients treated with tranexamic acid for weeks to months in clinical 
trials. 
Convulsions have been reported in association with tranexamic acid 
treatment, particularly in patients receiving tranexamic acid during 


 
 
 
 
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cardiovascular surgery and in patients inadvertently given tranexamic 
acid into the neuraxial system.  
Ureteral obstruction due to clot formation in patients with upper 
urinary tract bleeding has been reported in patients treated with 
tranexamic acid. 
Gastrointestinal disturbances including nausea, vomiting, and diarrhea 
may occur but disappear when the dosage is reduced.  Allergic 
dermatitis, giddiness and hypotension have been reported occasionally.  
Hypotension has been observed when intravenous injection is too 
rapid.  To avoid this response, the solution should be not be injected 
more rapidly than 100 mg/min. 
Thromboembolic events such as deep vein thromboses (DVTs) and 
pulmonary embolism (PE) are associated with trnexamic acid use. 
6.3.2. Known Potential Benefits 
Several studies as discussed in Section 6.2 show that tranexamic acid 
can reduce perioperative blood loss and accidental trauma. 
 
 


 
 
 
 
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7. TRIAL OBJECTIVES AND PURPOSE 
The purpose of this study is to assess the efficacy and safety of tranexamic acid 
using a dosage regimen similar to that used in the currently approved indication 
(intravenous therapy of patients with hemophilia during and following tooth 
extraction) for the reduction of blood loss and minimizing transfusion rates in 
patients undergoing spinal fusion surgery. This study will be used to support 
registration and labeling of Exela’s Tranexamic Acid products for use in the 
United States for this indication. 
 
 


 
 
 
 
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8. TRIAL DESIGN 
8.1. Description of Study Design 
A schedule of procedures and assessments is displayed in Section 4. 
 
This will be a multicenter, randomized, double-blind, parallel group study 
comparing tranexamic acid (test) to placebo (control) for reduction of 
perioperative blood loss after complex spinal fusion surgery (defined as spinal 
fusion surgery in the T2 to Pelvis/Sacrum area involving more than 4 Functional 
Spinal Units (4 discs/motion segments=5 Vertebral segments)). In addition to 
test and control treatments, all patients undergoing spinal fusion surgery will 
receive anesthesia and standard of care for blood loss including 
colloid/crystalloid fluid replacement and packed red cells, if necessary, 
according to a common multi-institutional protocol. Anesthesia will keep the 
mean arterial pressure as low as safe for the patient during exposure of surgery 
(estimated at 60-80 MAP). Patients will be randomized to receive either 30 
mg/kg tranexamic acid loading dose as a one hour infusion (3 mL/kg) prior to 
start of procedure and as an infusion at 3 mg/kg/h (0.3 mL/kg/h) of tranexamic 
acid throughout the surgery in the test group; or, a one hour infusion at 3 mL/kg 
of 0.9% saline prior to start of the procedure and an infusion of 0.9% saline at 
0.3 mL/kg/h in the control group. The maximum dose will be 50 mg/kg. 
 
The active phase of the study will be for the duration of hospital stay 
postoperatively for efficacy measurements and at 6 weeks for safety follow-
up. The randomization will be open only to the statistician generating the 
randomization sequence. All PI(s), study conduct and monitoring staff, as well 
as the subjects will be completely blinded to the treatments except in the case 
of emergency. An analyzable patient is one who satisfies admission criteria 
and who completes all required assessments. 
 
8.2. Study Endpoints 
8.2.1. Primary Endpoints 
The primary endpoints of this trial are to assess: 


 
 
 
 
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1. Total Blood Loss based on changes in hemoglobin (Blood loss 
will be calculated by Nadler’s and Gross’s formulae from the 
time of admission to hospital until discharge; Hemoglobin and 
hematocrit concentrations will be measured pre-operatively, 
post-operatively, and at 24 h and every 24h thereafter until 
discharge). 
2. Incidence of autologous or allogenic blood transfusion, 
including red blood cells and coagulation components (such as 
fresh frozen plasma and platelets). 
8.2.2. Secondary Endpoints 
The Secondary endpoints include assessment of: 
 
1. Total Measured Blood Loss (measured intra-operatively and 
for up to 24 hours post-operatively and every 24 hours up to 
discharge when the two subfascial drains are removed). Total 
Measured Blood Loss will be estimated as 3 times cell saver. 
 
 
2. Number of patients with symptomatic anemia (such as 
tachycardia, hypotension, presyncope) of <8.0 g/dL 
hemoglobin, or any hemoglobin <7.0 g/dL, precipitated 
transfusion. [Alternatively, allogenic blood transfusion will be 
considered for hemoglobin <9 g/dL intraoperatively or <8 
g/dL post-operatively] 
 
3. Number of patients with adverse events related to tranexamic 
acid such as confirmed deep vein thrombosis (DVT), 
pulmonary embolism (PE), or seizures. 
 
4. Other outcomes will include functional recovery, duration of 
hospital stay, and wound complications (infections, 
hematomas, and other complications related with surgery). 
 
8.3. Study Population 


 
 
 
 
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8.3.1. Inclusion Criteria 
Subjects must meet the following inclusion criteria: 
1. All adult patients (Male or Female) over age eighteen (>18) 
electively undergoing complex spinal fusion surgery (defined 
as T2 to Pelvis/Sacrum and greater than 4 Functional Spinal 
Units (4 discs/motion segments=5 Vertebral segments). 
2. Female subjects of childbearing potential with a negative 
serum (beta human chorionic gonadotropin [HCG]) pregnancy 
test at screening and urine pregnancy test at each admission; 
who are not breastfeeding; do not plan to become pregnant 
during the course of the study; and agree to use an approved 
method of birth control, such as condoms, foams, jellies, 
diaphragm, intrauterine device, sexual abstinence for at least 3 
months prior to study; 
3. Able to provide written informed consent after risks and 
benefits of the study have been explained; 
4. Able to communicate effectively with study personnel. 
8.3.2. Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from 
the study: 
1. History or presence of any clinically significant (based on the 
Investigator’s judgment) cardiovascular, respiratory, metabolic, 
hepatic, gastrointestinal, renal, hematological, dermatological, 
neurological, or psychiatric disease or condition preventing the 
use of tranexamic acid as described in this protocol; 
2. History of renal failure or elevated creatinine above 1.4; 
3. Any diagnosis of spinal tumor or intradural pathology; 


 
 
 
 
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4. Diagnosis of ankylosing spondylitits; 
5. History or presence of acquired disturbance of color vision; 
6. History of seizures; 
7. History of thromboembolic event (DVT or PE) within the past 
year 
8. Current use of anticoagulant medications or past medical history 
leading to an abnormal coagulation profile preoperatively;  
9. Subjects diagnosed with fibrinolytic disorders requiring intra-
operative antifibrinolytic treatment; hematological disease 
(thromboembolic events, hemoglobinopathy, coagulopathy, or 
hemolytic disease). 
10. Significant drug sensitivity or significant allergic reaction to any 
drug, including tranexamic acid, based on the Investigator’s 
judgment; 
11. A subject who has donated or lost 450 mL or more blood volume 
(including plasmaphoresis) or had a transfusion of any product 
within 3 months prior to the initial study drug administration. 
12. Pre-operative anemia (hb <110 in females, Hb <120 in males); 
13. Any subject that choses to refuse blood products for ethical or 
religious purposes (Jehovah’s Witness); 
14. Current participation in a drug or other investigational research 
study or participation within 30 days prior to the initial study 
drug administration. 
15. A subject who may not be able to comply with the safety 
monitoring requirements of this clinical trial or is considered by 
the investigator, for any reason, to be an unsuitable candidate for 
the study. 


 
 
 
 
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16. Intraoperative cardiovascular, pulmonary, orthopedic, or 
anesthetic complication such as myocardial infarction, 
intraoperative fracture, vasopressor support or emergent 
intubation. 
17. Female patients who are using combination hormonal 
contraception. 
18. Patients with history of subarachnoid hemorrhage. 
19. Patients with serum creatinine above ULN. 
8.3.3. Withdrawal Criteria 
Subjects will be discontinued from the study prematurely if: 
 
1. The subject requests to be withdrawn from the study; 
2. A need for a concomitant medication prohibited by the protocol 
arises; 
3. The Principal Investigator decides that it is in the subject's best 
interest; 
4. The subject is incompliant with the protocol; 
5. The subject experiences an adverse event that requires 
premature withdrawal.  
 
8.4. Randomization and Blinding 
When the subjects meet admission criteria and provide written informed 
consent, they will receive a subject number and be randomized by subject 
number into one of two treatment arms. They will receive either tranexamic 
acid or normal saline according to the randomization schedule. The 
randomization schedule will be generated prior to study initiation by a 
statistical programmer. The pharmacy will perform and document the 
randomization.   


 
 
 
 
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Subjects will be treated according to a randomization schedule prepared prior 
to the start of the study. The investigator site personnel as well as Exela 
personnel involved in the monitoring or conducting of the trial will be 
blinded to the trial drug codes (or kit codes), except in the case of an 
emergency.  Trial drug codes will not be available to the above personnel 
until after the completion of the trial and final data review. 
An individual decoding unit containing emergency identification of the kit 
contents will be provided for each kit. 
i. 
This decoding unit must not be opened unless an actual emergency 
occurs. The investigator should also make a careful note of the date, 
time of opening, and the reason. 
 
ii. 
In the event that a decoding unit is opened, the Exela monitor must be 
notified immediately by the investigator. 
 
iii. 
At the conclusion of the trial, all decoding units are to be returned to 
Exela together with unused drug supplies. 
 
 
 
 


 
 
 
 
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9. STUDY AGENT 
9.1. Study Agent(s) Administration 
9.1.1. Study Agent(s) Description 
Test Drug: Exela’s Tranexamic Acid Intravenous Infusion Bags (10 
mg/mL), manufactured and provided by Exela Pharma Sciences, LLC 
from a single batch / lot will be administered to all randomized 
subjects. 
Test Placebo: Inactive ingredient mixture for injection without drug, 
intravenous infusion bags containing normal saline, manufactured and 
provided by Exela Pharma Sciences, LLC from a single batch / lot will 
be administered to all randomized subjects. 
 
9.1.2. Dosing and Administration 
Infuse 3 mL/kg over one hour followed by continuous infusion at 0.3 
mL/kg for maximum infusion volume of 5 mL/kg.  
9.1.3. Formulation, Appearance, Packaging, and Labeling 
The trial drugs will be supplied as kits containing seven (7) identically 
appearing intravenous bags containing 100 mL of an intravenous 
solution.  Each bag will have a label affixed to it which states the kit-
number, bag-number, and directions. A single kit will be used for each 
subject and will contain tranexamic acid infusion bags or saline bags.  
[The number of bags per kit can be changed depending on the longest 
anticipated surgery time and/or the anticipated highest subject weight] 
9.2. Preparation/Handling/Storage/Accountability 
9.2.1. Acquisition and Accountability 


 
 
 
 
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The Principal Investigator will maintain accurate records of receipt of 
all test articles, including dates of receipt. In addition, accurate records 
will be kept regarding when and how much of each test article is 
dispensed to and used by each individual subject in the study. Reasons 
for deviation from the expected dispensing regimen must also be 
recorded. A Drug Dispensing Form will be provided for this purpose 
and will be signed by the Principal Investigator at the conclusion of the 
study. 
9.2.2. Product Storage and Stability 
Tranexamic Acid Injection (10 mg/mL) should be stored at controlled 
room temperature (20 – 25 ºC; or 68 – 77 ºF). Under these conditions 
Tranexamic Acid Injection (10 mg/mL) is stable for 2 years from date 
of manufacture. 
 
9.2.3. Preparation 
Tranexamic Acid Injection (10 mg/mL) is suitable for direct 
administration and no additional preparation is necessary. 
 
9.2.4. Retention Samples 
Retention (reserve) samples of the test formulations will be selected and 
retained by the Principal Investigator (or Investigational Pharmacist) in 
a locked, secure pharmacy cabinet in compliance with the individual 
clinical site SOP requirements.  
 
The retention period is to be at least five years following the date on 
which a full or abbreviated NDA or supplemental application is 
approved, or if not approved, at least five years following the 
completion of a bioavailability/bioequivalence study.  To ensure 
compliance, Exela/SpineMark will conduct a yearly audit.  The drugs 
will be stored under specified conditions in a designated storage area, 
locked and with limited access.  The investigator will be informed by 


 
 
 
 
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Exela/SpineMark at the appropriate time when and how to return the 
retention samples. 
 
10. STUDY PROCEDURES AND SCHEDULE 
10.1. Study Procedures/Evaluations 
10.1.1. Study Specific Procedures 
Vital Signs Assessments 
 
Vital signs will be monitored just prior to and during surgery and any 
abnormal vital signs result that is considered clinically significant by the 
Investigator will be recorded as an adverse event. 
 
Physical Examination 
 
A full physical examination will be performed at the screening visit 
and prior to discharge from the study or at early termination. A full 
physical examination includes assessment of general appearance and 
evaluation of dermatological system, head, eyes, ears/nose/throat, 
neck, lymph nodes, lungs, heart, abdomen, neurological, and 
musculoskeletal system.  
10.2. Laboratory Procedures/Evaluations 
10.2.1. Clinical Laboratory Evaluations 
Hematology, chemistry including metabolic profile and urinalysis 
evaluations will be performed at the pre-operative screening visit and 
prior to discharge from the study. An abnormal clinical laboratory test 
result that is considered clinically significant by the Investigator will 
be recorded as an adverse event and follow-up clinical laboratory 
evaluations may be performed at the discretion of the Investigator. 
 


 
 
 
 
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Hemoglobin content of the collected blood samples will be done by 
the clinic site or an accredited lab. Hematocrit concentration of the 
collected blood samples will also be determined. 
 
Clinical chemistry assessments will be done by the clinic site or an 
accredited lab.    
 
10.2.2. Other Assays or Procedures 
No other assays or procedures are planned for this study 
10.2.3. Specimen Preparation, Handling, and Storage 
Blood samples for hemoglobin measurement will be collected prior to 
start of procedure, at the end of the procedure, at 24 h, and every 24 h 
thereafter until discharge. Hematocrit analysis will also be conducted on 
all collected blood samples.  
 
Blood lost during surgery will be collected by subfascial Hemovac 
drains at the incision site into canisters containing heparinized saline. 
Volumes collected will be recorded post-surgery and every 24 h 
thereafter until discharge and removal of the two subfascial drains.   
 
10.2.4. Specimen Shipment 
Each clinical site will have established procedures for sample 
shipment as necessary. 
10.3. Study Schedule 
10.3.1. Screening 
Prior to surgery, subjects will provide written informed consent and 
will then undergo pre-operative data collection/screening, including: 
• Inclusion Exclusion criteria assessment 
• Diagnosis leading to surgery 
• Planned procedure 


 
 
 
 
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• Schwab Curve type and coronal curve magnitude (Cobb angle) 
• Patient age and demography 
• Height, Weight, and Body Mass Index 
• Number of units of autologous blood donation 
• CBC: Hb/Hct/WBC/platelet count (post-autologous donation) 
• Coagulation Profile: PT/PTT/INR 
• Medical History and Medication Use 
• History of Previous Spine Surgery 
• Drug / Alcohol / Tobacco Use 
• Medication Allergies 
• Pregnancy testing (females only) 
 
10.3.2. Pre-Treatment Procedures 
A urine pregnancy test will be performed (females only). 
10.3.3. Drug Dosing 
Blinded treatments will be administered at an initial dose of 3 mL/kg 
as a one hour infusion using a calibrated infusion pump prior to start of 
procedure, and as a 0.3 mL/kg/h infusion during surgery up to a 
maximum infusion volume of 5 mL/kg.  Each treatment will be 
administered by a calibrated infusion pump. The pump’s manufacturer, 
model, and serial number will be recorded on the CRF. The volume 
infused remains constant regardless of whether the patient is receiving 
tranexamic acid or saline.   
 
At the termination of the trial, all unused trial medication must be 
returned to Exela Pharma Sciences. Instructions for the return of trial 
medication will be provided by Exela at the completion of the trial. 
 
Blood samples for hemoglobin measurement will be collected prior to 
start of procedure, at the end of the procedure, at 24 h, and every 24 h 
thereafter until discharge.  Hematocrit analysis will also be conducted 
on all collected blood samples. 


 
 
 
 
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The following data will also be recorded: 
• Treatment ID 
• Details of surgical procedure [Number of vertebrae fused, 
number of anchors used, and type of anchors used (screws, 
hooks, or anchors); Number and type of osteotomies 
performed] 
• Any complication prolonging the surgery time or increasing 
patient blood loss 
• Surgery time 
• Estimated blood loss peri-operatively (from drainages and 
absorbent/surgical pads) 
• Volume of cell saver delivered 
• Units of autologous transfusion and allogenic transfusion 
• Units of fresh frozen plasma and platelets administered 
• Volume of crystalloids/colloids given 
• Urine output 
• Location of Hemovac drains and number of drains placed 
• Drain output recorded daily 
• Length of drain use (uniformly remove drains when output 
<120 mL/day) 
• Length of hospital stay 
• Complications of autologous or allogenic transfusion 
• Complications of tranexamic acid including renal, hepatic, 
thromboembolic, and brain/CNS 
• Functional recovery assessments will be completed prior to 
discharge 
• Any wound complications for the duration of hospitalization 
 
 
 
10.3.4. Follow-Up Procedures 


 
 
 
 
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Follow-ups on wound complications and on adverse events related to 
tranexamic acid (such as seizures, DVTs, and PEs) will be conducted 
minimally every 24 h during hospital stay and at 6 weeks. 
 
Adverse events (AEs) will also be monitored by the investigator and/or 
designated research staff and spontaneous reporting throughout the 
study. 
 
10.3.5. Final Study/Early Termination Visit 
Subjects who complete the study will have procedures collected as 
described in Period 2. If a subject withdraws early from the study, the 
same information will be collected as follows: 
a. A final physical examination will be done. 
 
b. Sitting vital signs blood pressure, pulse, and temperature will 
be obtained. 
 
c. Specimens for safety laboratory tests will be obtained. 
 
d. The subject will be asked if he/she had any adverse 
experiences.    
If a subject withdraws from the study at any time, either at his or her 
request or at the Principal Investigator’s discretion, the reason(s) for 
withdrawal will be recorded on the relevant page of the source. All final 
visit tasks (discharge procedures) will be completed for all subjects who 
withdraw from the study. Withdrawn subjects may be replaced at the 
Sponsor’s discretion. Subjects withdrawn due to AEs will be monitored 
until resolution or stabilization of the AE or until 30 days from the initial 
report of the AE, whichever occurs first. 
If a subject is discontinued, the following consistent terminology will 
be used to capture this information on the CRF: 


 
 
 
 
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• Death 
• Lost to Follow-up 
• Adverse Event 
• Non-Compliance with Study Drug 
• Physician Decision 
• Protocol Violation 
• Study termination by Sponsor 
• Withdrawal of Consent 
10.4. Concomitant Medications, Treatments, and Procedures 
The use vitamin K, aspirin or aspirin containing products are prohibited 
once a subject is entered into this trial.  All other concomitant medications 
are to be recorded.  
Any prescription or over-the-counter medication taken during the study 
will be recorded in the appropriate section of the source document. Any 
over-the-counter or prescription medications taken during the study will 
be recorded as a protocol deviation. 
10.5. Efficacy Assessments 
The primary objectives of this trial are to assess: 
1. Total Blood Loss (based on hemoglobin changes). 
2. Incidence of autologous or allogenic blood transfusion, including 
red blood cells and coagulation components (such as fresh frozen 
plasma and platelets). 
Total Blood Loss will be determined using Gross’s formula11 as 
follows: 
𝑉𝐿=  𝐸𝐵𝑉 x (𝐻𝑐𝑡0 −𝐻𝑐𝑡𝑓
𝐻𝑐𝑡𝑎𝑣
) 


 
 
 
 
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Where VL is the volume of total calculated blood loss, EBV is the 
estimated blood volume from Nadler’s formula, Hct0 is the hematocrit 
before surgery, Hctf is the hematocrit at 24 h or discharge/48 h after 
wound closure and Hctav is the average of Hct0 and Hctf. 
Nadler’s formula12 is, 
Male:  0.3669 ∙ (height)3 + 0.03219 ∙ (weight) + 0.6041, and  
Female:  0.3561 ∙ (height)3 + 0.03308 ∙ (weight) + 0.1833, 
where, height is in meters and weight is in kilograms. 
Secondary efficacy objectives include assessment of: 
1. Total measured blood loss (measured intra-operatively and for up 
to 24 hours post-operatively and every 24 hours up to discharge 
when the two subfascial drains are removed). Measured Blood 
Loss will be estimated as 3 times Cell Saver. 
2. Number of patients with symptomatic anemia (such as tachycardia, 
hypotension, presyncope) of <8.0 g/dL hemoglobin, or any 
hemoglobin <7.0 g/dL, precipitated transfusion. [Alternatively, 
allogenic blood transfusion will be considered for hemoglobin <9 
g/dL intraoperatively or <8 g/dL post-operatively] 
 
3. Number of patients with adverse events related to tranexamic acid 
such as confirmed deep vein thrombosis (DVT), pulmonary 
embolism (PE), or seizures. 
 
4. Other outcomes will include functional recovery, duration of 
hospital stay, and wound complications (infections, hematomas, 
and other complications related with surgery). 
 
10.6. Safety and Other Assessments 


 
 
 
 
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Safety assessments will include monitoring of AEs, functional recovery 
assessments, wound complications, length of hospital stay, blood loss, and 
transfusions. 
Adverse events will be monitored by the observations of the principal 
investigator and medical staff and/or spontaneous reporting throughout the 
study. 
10.7. Adverse Events and Serious Adverse Events 
10.7.1. Definitions 
Adverse Event – Any untoward medical occurrence in a clinical 
investigation subject administered a drug and does not necessarily have 
a causal relationship with this treatment. An AE can therefore, be any 
unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not related to the investigational 
product. 
 
Suspected Adverse Reaction – any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the 
purposes of IND safety reporting, "reasonable possibility" means there 
is evidence to suggest a causal relationship between the drug and the 
adverse event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any 
adverse event caused by a drug. 
 
Serious Adverse Event (SAE) – Any experience that is fatal or life-
threatening, requires or prolongs inpatient hospitalization, results in 
persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions, is a congenital anomaly or birth defect, 
or an important medical event that, based upon appropriate medical 
judgment, may jeopardize the subject and may  require medical or 
surgical  intervention to prevent one of the outcomes listed in this 
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Unexpected Adverse Event/Suspected Adverse Reaction – Any 
adverse event or adverse reaction that is not identified in nature, 
severity, or frequency in the Product Labeling.1 
10.7.2. Classification of an Adverse Event 
The Principal Investigator will evaluate all AEs as follows: 
Seriousness: whether or not the AE is fatal or life threatening, persistent 
or permanently disabling, requires or prolongs inpatient hospitalization, 
is a congenital anomaly or an important medical event or requires 
medical intervention to prevent one of the above outcomes 
Action taken: whether or not the AE caused the subject to discontinue 
the study drug, or use a concomitant medication 
Intensity, to be graded as: 


 
 
 
 
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DEGREE 
DESCRIPTION 
Mild 
Awareness of signs and symptoms; easily tolerated 
Moderate 
Discomfort sufficient to interfere, but not prevent 
daily activity 
Severe 
Unable to carry out usual activity 
 
Relationship to study drug, to be graded as: 


 
 
 
 
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DEGREE 
DESCRIPTION 
Not related 
The experience is clearly related to 
other factors such as the subject’s 
clinical state, therapeutic interventions 
or concomitant drugs administered to 
the subject. 
Unlikely 
The experience was most likely 
produced by other factors such as the 
subject’s clinical state, therapeutic 
interventions or concomitant drugs 
administered to the subject which do 
not follow a known response pattern to 
the trial drug. 
Possible  
The experience follows a reasonable 
temporal sequence from the time of 
drug administration, and/or follows a 
known response pattern to the trial 
drug, but could have been produced by 
other factors such as the subject’s 
clinical state, therapeutic interventions 
or concomitant drug administered to 
the subject. 
Probable 
The experience follows a reasonable 
temporal sequence from the time of 
drug administration, and follows a 
known response pattern to the trial 
drug, and cannot be reasonably 
explained by other factors such as the 
subject’s clinical state, therapeutic 
interventions or concomitant drugs 
administered to the subject 


 
 
 
 
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Related 
The experience follows a reasonable 
temporal sequence from the time of 
drug administration, and follows a 
known response pattern to the trial 
drug, and cannot be reasonably 
explained by other factors such as the 
subject’s clinical state, therapeutic 
interventions or concomitant drugs 
administered to the subject, and either 
occurs immediately following trial 
drug administration,  or improves on 
stopping the drug, or reappears on 
repeat exposure, or there is a positive 
reaction at the application site. 
 
10.7.3. Adverse Event and Pregnancy Follow-Up 
The Investigator should take all appropriate measures to ensure the 
safety of the subjects, including referral to a specialist if indicated. The 
Investigator should follow up on the outcome of any AE (including 
SAEs) until the event has resolved or stabilized, or until 30 days from 
the initial report of the AE, whichever occurs first. 
Any pregnancy that occurs in a subject or the partner of a subject on 
study drug must be reported to the Sponsor within 24 hours of learning 
of its occurrence. The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the 
birth and presence or absence of any birth defects, congenital 
abnormalities or maternal and/or newborn complications. 
 
Any SAE brought to the attention of the Investigator within 30 days 
after cessation of study drug should be reported through the SAE 
reporting process. 
 
10.7.4. Adverse Event Reporting 


 
 
 
 
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Any AE (clinical sign, symptom, or disease) temporally associated 
with the use of this investigational product, whether or not considered 
related to the investigational product, should be documented on the 
source document. All AEs reported by the subject or observed by the 
Principal Investigator will be individually listed. The signs and 
symptoms, time of onset (24-hour clock), duration, action taken and 
follow-up procedures will be reported. 
10.7.5. Serious Adverse Event Reporting 
The Principal Investigator shall document all AEs. He/she must report 
(by phone, email, etc.) any SAE to the Sponsor or its designee and to 
any IRB (Institutional Review Board) that has reviewed and is 
continuing to review the investigation within 24 hours of the first 
knowledge of the occurrence.  
Fatal or life-threatening occurrences in clinical investigations qualify 
for very rapid reporting. Regulatory agencies should be notified (e.g., 
by telephone, facsimile transmission, or in writing) as soon as possible 
but no later than 7 calendar days after first knowledge by the sponsor.  
 
Serious adverse events that are not fatal or life-threatening must be filed 
as soon as possible but no later than 15 calendar days after first 
knowledge by the Sponsor that the case meets the minimum criteria for 
expedited reporting. 
For any SAE, the Principal Investigator must notify the contact 
persons listed below within 24 hours: 
 
Sponsor contact information 
Jason Liu, PharmD 
1245 Blowing Rock Blvd. 
PO box 818 Lenoir, NC  28645 
Tel: (828) 758-5474 ext. 181 
Email: jliu@exela.us 
 
Aruna Koganti, PhD, MBA 
1245 Blowing Rock Blvd. 


 
 
 
 
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PO box 818 Lenoir, NC  28645 
Tel: (828) 758-5474 ext. 181 Cell:  410-370-2375 
Email:  akoganti@exela.us 
 
Principal Investigators will be responsible for reporting any SAEs to 
the Sponsor, who report them to the FDA. 
 
11. STATISTICAL CONSIDERATIONS 
11.1. Statistical Hypothesis 
The null hypothesis (H0) is that there is no difference between the two 
groups. The alternative hypothesis (H1) is that the two groups are 
significantly different. 
11.2. Sample Size Determination 
Assuming a two-sided alpha level of 0.05, 80% power and estimated mean 
blood loss of 2000 mL in the control group (with a relatively low estimated 
standard deviation of 1000 mL due to limitations in the type of surgery and 
the patient population) a 25% decrease in blood loss in the treated group 
would require 128 patients (64 per group).  Thus, the proposed sample size 
of 150 patients (100 active and 50 placebo) will allow 14.7% loss to follow-
up which should be sufficient considering the relatively small likelihood of 
loss to follow-up in these patients. 
 
11.3. Populations for Analysis 
Up to approximately 150 patients will be enrolled.  
 
The primary analysis population will be a modified Intent to Treat (mITT) 
population consisting of all subjects receiving an injection of TXA or 
Placebo.  
 
The secondary analysis population will be a Per Protocol (PP) population 
consisting of all subjects without major protocol violations (to be 


 
 
 
 
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determined by a blinded committee prior to breaking the double-blind 
code).  
 
The safety population will consist of all subjects receiving an injection of 
TXA or placebo. 
 
 
11.4. Statistical Analysis 
11.4.1. General Approach 
Data from multiple centers are intended to be combined under this 
protocol so that an adequate number of patients/subjects will be 
available for analysis. 
 
Comparability of treatment groups based on demographic and baseline 
characteristics of the patients/subjects will be evaluated by appropriate 
statistical tests. 
 
All hypothesis-testing analyses will be performed at the two-sided 
significance level of 5% (=0.05). 
 
11.4.2. Analysis of Primary Efficacy Endpoint(s) 
The primary efficacy variable will be total blood loss as described in 
Section 10.1.  Since blood loss will be measured up to 24 hours after 
surgery and over the entire period of hospitalization, the primary 
measure will be the 24-hour level.  Blood loss at later time-points will 
only be considered significant if the 24-hour measure has also reached 
statistical significance.  Due to the hierarchical structure of this 
analysis, no adjustment for multiplicity will be performed. 
 
The primary efficacy variables and continuous secondary efficacy 
variables will be analysed using Analysis of Covariance (ANCOVA) 
where one factor is treatment (TXA vs Placebo) and the other factor is 
Surgeon.  The initial analysis will include the interaction between the 


 
 
 
 
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two factors in order to assess the similarity of effects across surgeons.  
Significant interaction effects will occur if (for example), TXA works 
for some surgeons but not for others.  The final efficacy analysis will 
remove the interaction term and control for overall differences 
between surgeons. 
 
11.4.3. Analysis of Secondary Efficacy Endpoint(s) 
Secondary efficacy variables will include the following. 
 
1. Blood loss measured as 3 times cell saver.   
 
 
Also included as secondary efficacy variables will be several outcomes 
normally treated as adverse events. 
 
1. Incidence of symptomatic anemia as defined in Section 10.1. 
Categorical secondary efficacy variables will be similarly analysed 
using multiple logistic regression analyses.  If incidences are low, 
analyses of interaction effects may not be possible and Cochran-
Mantel-Haenszel tests will be used instead. 
11.4.4. Safety Analysis 
Adverse events will be categorized using MedDRA codes. The TXA 
and placebo groups will be compared using Fisher exact tests of the 
number of patients with each category of adverse events.  The total 
number of reported adverse events will also be presented. 
11.4.5. Baseline Descriptive Statistics 
In general, continuous variables will be analyzed using Student’s t test, 
binary variables will be analyzed using the Fisher exact test and 
ordered categorical variables will be analyzed using the Wilcoxon 
rank-sum test. 
11.4.6. Planned Interim Analysis 


 
 
 
 
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None planned 
11.4.7. Sub-Group Analysis 
Exploratory subgroup and covariance analyses may also be performed 
11.4.8. Tabulation of Individual Participant Data 
Tabulations of individual patient data will be included in the final 
report. 
11.4.9. Exploratory Analysis 
Exploratory subgroup and covariance analyses may also be performed 
 
 
 
 


 
 
 
 
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12. REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
12.1. Informed Consent Process 
A properly executed, written informed consent in compliance with Food 
and Drug Administration (FDA) regulations and Good Clinical Practice 
(GCP) guidelines will be obtained from each subject prior to entering the 
study or performing any unusual or non-routine procedure that involve a 
risk to the subject. The Principal Investigator will submit a copy of the 
informed consent document to the IRB for review and approval before 
research subjects are enrolled. The Principal Investigator will provide a 
copy of the signed informed consent to the subject and a copy will be 
maintained in the subject's medical record. 
The Principal Investigator will provide the IRB with all requisite material, 
including a copy of the informed consent. The study will not be initiated 
until the IRB provides written approval of the protocol and the informed 
consent. Appropriate reports on the progress of this study by the Principal 
Investigator will be made to the IRB and the Sponsor in accordance with 
the applicable government regulations and in agreement with policy 
established by the Sponsor. 
12.2. Confidentiality and Privacy 
All information provided to the Principal Investigator by the Sponsor or 
their designees, including non-clinical data, protocols, source documents 
and verbal and written information, will be kept strictly confidential and 
confined to the clinical personnel involved in conducting the study. It is 
recognized that this information may be released in confidence to the IRB. 
In addition, no reports or information about the study or its progress will 
be provided to anyone not involved in the study other than to the Sponsor 
or their designees or in confidence to the IRB, except if required by law. 
12.3. Key Roles and Study Governance 
Study governance and ethical oversight: 


 
 
 
 
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Western Institutional Review Board  
Research Foundation 
Address: 1019 39th Ave SE #120, Puyallup, WA 98374 
Phone:(360) 252-2500 
12.4. Safety Oversight 
Study safety monitoring will be the primary responsibility of the Sponsor, 
Exela Pharma Sciences, LLC, and be coordinated with the CRO, 
SpineMark. 
 
 
Medical Safety oversight: 
  
Neel Anand, M.D. 
Clinical Professor of Surgery 
Cedars -Sinai Medical Center 
444 South San Vincente Boulevard, Ste 901 
Los Angeles, CA 90048 
Safety Coordinator: 
Tom Juarez 
Director, Regulatory and Quality 
SpineMark 
 
12.5. Clinical Monitoring 
SpineMark or their designee will monitor all aspects of the study with 
respect to current GCP and standard operating procedures for compliance 
with applicable federal regulations. These individuals will have access to 
all records necessary to ensure integrity of the data and will periodically 
review progress of the study with the Principal Investigator. 
12.6. Quality Assurance and Quality Control 
All data recorded during the study will be available for audit against source 
data and for compliance with GCP and specific protocol requirements. 
Monitoring of the study progress and conduct will be ongoing.  


 
 
 
 
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The Principal Investigator will be responsible for the following: 
 
1. Monitoring study conduct to ensure that the rights of subjects are 
protected; 
 
2. Monitoring study conduct to ensure trial compliance with GCP 
guidelines; and 
 
3. Monitoring accuracy, completion and verification from source 
documents of study data. 
 
12.7. Data Handling and Record Keeping 
12.7.1. Data Collection and Management Responsibilities 
Data collection and management: 
SpineMark, Inc. will be responsible for data collection, management, 
and control per internal Standard Operating Procedures.  
Biostatistician: 
Fred Hoehler, Ph.D 
12.7.2. Study Records and Retention Samples 
Principal Investigator will keep all study-related documentation in 
accordance with FDA, GCP guidelines and SOP. At that time, the 
Principal Investigator will contact the Sponsor regarding further 
disposition of the study records and retention samples comply with 
instructions provided by the Sponsor. No property will be disposed of 
without the consent of the sponsor. 
12.8. Protocol Deviations 
Protocol deviation will be documented with the study data and reported to 
the Sponsor on a regular basis. 
12.9. Publication and Sharing Policy 


 
 
 
 
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Following completion of the study, the data from this study may be 
considered for reporting at a scientific meeting or for publication in a 
scientific journal at the sole discretion of the Sponsor. In the case whereby 
the results of this study are to be published, the Sponsor will be 
responsible for these activities and will work with the Principal 
Investigator(s) to determine how the manuscript is written and edited, the 
number and order of authors, the publication to which it will be submitted 
and other related issues. 
12.10. Final Report 
A final summary report will be issued to the Sponsor by SpineMark. 
Where applicable, it will contain a narrative description of the clinical, 
analytical, pharmacokinetic and statistical procedures used during the 
conduct of the study. Appropriate tables and graphs will be created to 
summarize the data. 
 
 
 
 


 
 
 
 
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13. PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change 
Brief Rationale 
1.0 
Sep 18, 
2017 
Initial protocol finalization 
N/A 
1.1 
Nov 21, 
2017 
Removal of PIs and study 
sites that have opted out. 
Change spinal anesthesia to 
anesthesia 
Administrative changes.  
There is no way to do major 
surgery under spinal 
anesthesia, therefore, the 
change from spinal anesthesia 
to anesthesia has been made 
1.2 
Nov 29, 
2017 
Reduce number of bags per 
kit from 10 to 7 
Table in Section 9.2.1  
 
 
Number 
of 
Patients 
100 
50 
Inventory constraints. 
 
Correct error in the table in 
section 9.1.2 to reflect 2:1 
TXA:placebo allocation 
1.3 
Dec 22, 
2017 
Changes to Primary and 
Secondary endpoints 
Additions to Exclusion 
Criteria 
Corrections for consistency 
throughout the protocol 
Changes made as per FDA 
reviewer comments and 
recommendations 
1.4 
Mar 23, 
2018 
Removed instances of 
hemoglobin and hematocrit 
measurements on blood 
collected from drainages 
Replaced Dr. Verma with Dr. 
Saigal as PI 
Measurements are not 
necessary. Dr. Verma has 
resigned from his position at 
UW. 
 
 
1.5 
May 15, 
2018 
Replace Dr. Saigal with Dr. 
Hershman as PI for site 4 
UW has dropped out of the 
study. Massachusetts General 


 
 
 
 
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Hospital with Dr. Hershman as 
PI will replace UW. 
1.6 
May 29, 
2018 
Replace Dr. Thomas Errico 
with Dr. Aaron Buckland 
Dr. Thomas Errico has retired 
 
 


 
 
 
 
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14. REFERENCES 
1. CRASH-2 trial collaborators, Effects of tranexamic acid on death, vascular 
occlusive events, and blood transfusion in trauma patients with significant 
haemorrhage (CRASH-2): a randomized, placebo-controlled trial, 
www.thelancet.com, published online June 15, 2010; DOI:10.1016/S0140-
6736(10)60835-5. 
2. CYKLOKAPRON Package Insert 
3. Shapiro F, Zurakowski D, and Sethna NF, Tranexamic acid diminishes 
intraoperative blood loss and transfusion in spinal fusions for Duchenne 
muscular dystrophy scoliosis, Spine, 32 (20): 2278-2283, 2007. 
4. Wong J, El Beheiry H, Rampersaud YR, Lewis S, Ahn H, De Silva Y, et al. 
Tranexamic Acid reduces perioperative blood loss in adult patients having 
spinal fusion surgery. Anesthesia and analgesia. 107(5):1479–86, 2008. 
5. Grant JA, Howard J, Luntley J, Harder J, Aleissa S, and Parsons D, 
Perioperative blood transfusion requirements in pediatric scoliosis surgery: 
the efficacy of tranexamic acid, Journal of Pediatric Orthopedics, 29(3): 300-
304, 2009. 
6. Verma K, Kohan E, Ames CP, Cruz DL, Deviren V, Berven S, and Errico 
TJ, A comparison of two different dosing protocols for tranexamic acid in 
posterior spinal fusion for spinal deformity: A prospective, randomized trial, 
International Journal of Spine Surgery, 9(65): 1-9, 2015. 
7. Cheriyan T, Maier SP II, Bianco K, et al. Efficacy of tranexamic acid on 
surgical bleeding in spine surgery: a meta-analysis. Spine J. 15:752–761, 
2015. 
8. Winter F, SantaguidaC, Wong, J and Fehlings M . Systemic and topical use 
of tranexamic acid in spinal surgery: a systematic review. Global Spine J. 
06(03): 284-295, 2016. 


 
 
 
 
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9. Hunt BJ. The current place of tranexamic acid in the management of 
bleeding. Anaesthesia 70(1)(Suppl. 01): 50-53 , e18, 2015. 
10. Guinn NR, Broomer BW, White W, Richardson, W, and Hill SE, 
Comparison of visually estimated blood loss with direct hemoglobin 
measurement in multilevel spine surgery, Transfusion, 53: 2790-2794, 2013. 
11. Gross JB. Estimating allowable blood loss: Corrected for dilution.  
Anesthesiology 58:277-280, 1983. 
12. Nadler SB, Hidalgo JH and Bloch T. Prediction of blood volume in normal 
human adults.  Surgery 51:224-232, 1962. 
 
 


 
 
 
 
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15. PRINCIPAL INVESTIGATOR’S STATEMENT AND 
SPONSOR APPROVAL SIGNATURE 
I agree to conduct the study as outline in the protocol and in accordance with the 
Sponsor’s guidelines and Good Clinical Practice requirements. 
 
 
 
PI Name 
 
Date 
Title 
 
 
Organization 
 
 
 
 
PI Name 
 
Date 
Title 
 
 
Organization 
 
 
 
 
PI Name 
 
Date 
Title 
 
 
Organization 
 
 
 
 
PI Name 
 
Date 
Title 
 
 
Organization 
 
 
 
 


 
 
 
 
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Sponsor Approval Signature 
 
 
 
 
Name 
 
Date 
Title 
Sponsor Clinical Monitor 
 
 
Exela Pharma Sciences, LLC 
 
 
 
 
 
Sponsor Quality and Regulatory Approval Signature 
 
 
 
 
Name 
 
Date 
Title 
 
 
Sponsor Quality and Regulatory 
Monitor 
Exela Pharma Sciences, LLC 
 
 
 
 
 


 
 
 
 
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16. APPENDIX