Tranexamic Acid Dosing for Major Joint Replacement Surgery
Phase: PHASE2
Conditions: Arthroplasty, Replacement, Knee, Arthroplasty, Replacement, Hip
Sponsor: Sunnybrook Health Sciences Centre

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(TXA-Dosing) 
 
 Tranexamic Acid Dosing for Major Joint Replacement Surgery  
Prospective cohort study at Sunnybrook Health Sciences Center (SHSC) 
 
Protocol Number: 1567 
 
   
Principal Investigator: Dr. Angela Jerath 
Regulatory Sponsor: Sunnybrook Research Institute 
Funding Agency: Sunnybrook AFP Association through the Innovation Fund of the 
Alternative Funding Plan from the Academic Health Sciences Centre of 
Ontario 
Investigational Product: Tranexamic acid 
Coordinating Centre: 
 
 
 
 
 
 
 
Centre for Clinical Trial Support (CCTS) 
Sunnybrook Research Institute 
C8-2075 Bayview Avenue 
Toronto, ON M4N 3M5 
Canada 
Phone: (416) 480-4964 
Fax: (416) 480-6039 
 
  
  
  
  
Co-Investigators: 
Drs. Chris Idestrup, K.Sandy Pang, Jeannie Callum, Yulia Lin, Bheeshma 
Ravi, John Murnaghan, Stephen Choi, Beverley A. Orser 
 
  
 
 

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SPONSOR STATEMENT OF COMPLIANCE 
This study will comply with the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human use Good Clinical Practice E6 (ICH-GCP), World 
Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving 
Human Participants, as well as applicable regulatory and institutional requirements.  
 
Personnel listed below are authorized to sign the protocol and any subsequent protocol 
amendments on behalf of the sponsor:  
Name: 
(Print) 
Dr. Angela Jerath 
Title:  
(Print) 
Principal Investigator 
Signature: 
 
Date of Approval: 
(yyyy-mmm-dd) 
 
 

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PROTOCOL SIGNATURE PAGE 
 
I have read this protocol in its entirety and its appendices.  I agree to comply with the 
requirements of the study protocol and procedures for data recording/reporting and 
acknowledge my responsibility for the well-being of each research participant, and to ensure that 
all persons involved in study activities are adequately informed about the protocol, the 
investigational product, and their trial-related duties.  The signature below constitutes the 
agreement to conduct this study in accordance with the REB approved protocol, GCP and  
applicable regulatory requirements, including confidentiality, ethical guidelines and regulations 
regarding the conduct of research in humans. 
 
Principal Investigator: 
Name: 
(Print) 
Dr. Angela Jerath 
Title & Institution:  
(Print) 
Staff Anesthesiologist, SHSC 
Signature: 
 
Date of signature: 
(yyyy-mmm-dd) 
 
 

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TABLE OF CONTENTS 
PAGE 
SPONSOR STATEMENT OF COMPLIANCE ...................................................................................................... II 
PROTOCOL SIGNATURE PAGE ...................................................................................................................... III 
TABLE OF CONTENTS .................................................................................................................................... IV 
LIST OF ABBREVIATIONS ............................................................................................................................. VII 
PROTOCOL SUMMARY ................................................................................................................................. IX 
1 
KEY ROLES AND CONTACT INFORMATION .......................................................................................... 1 
2 
INTRODUCTION ................................................................................................................................... 2 
2.1 
Background ............................................................................................................................ 2 
2.2 
Clinical Data to Date ............................................................................................................... 2 
2.3 
Potential Risks/Benefits and Rationale .................................................................................. 3 
3 
STUDY OBJECTIVES .............................................................................................................................. 4 
3.1 
Primary Objective ................................................................................................................... 4 
3.2 
Secondary Objective(s) .......................................................................................................... 4 
4 
STUDY DESIGN ..................................................................................................................................... 5 
5 
PARTICIPANT SELECTION AND WITHDRAWAL .................................................................................... 7 
5.1 
Inclusion Criteria .................................................................................................................... 7 
5.2 
Exclusion Criteria .................................................................................................................... 7 
5.3 
Participant Recruitment ......................................................................................................... 7 
5.4 
Participant Withdrawal and Discontinuation of IP ................................................................ 8 
5.4.1 
Reasons for Withdrawal/Discontinuation of IP ........................................................ 8 
5.4.2 
Data Collection and Follow-up for Withdrawn Participants ..................................... 8 
6 
INTERVENTIONS .................................................................................................................................. 9 
6.1 
Investigational Product .......................................................................................................... 9 
6.1.1 
Acquisition, Formulation and Packaging ................................................................... 9 
6.1.2 
Treatment Assignment Procedures .......................................................................... 9 
6.1.3 
Dosage, Preparation and Administration .................................................................. 9 
6.1.4 
Dose Modification ..................................................................................................... 9 
6.1.5 
Receiving, Storage, Dispensing and Return .............................................................. 9 
6.1.6 
Prior and Concomitant Medications/Treatments ................................................... 10 
7 
STUDY SCHEDULE AND PROCEDURES ............................................................................................... 11 
7.1 
Screening .............................................................................................................................. 11 
7.2 
Baseline/Enrollment ............................................................................................................. 11 
7.3 
Study visits ........................................................................................................................... 11 
7.4 
Follow up .............................................................................................................................. 11 
7.5 
Protocol Deviations .............................................................................................................. 11 
8 
ASSESSMENT OF SAFETY ................................................................................................................... 13 
8.1 
Definitions ............................................................................................................................ 13 
8.1.1 
Adverse Events ........................................................................................................ 13 
8.1.2 
Serious Adverse Events ........................................................................................... 13 

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8.1.3 
Unexpected Adverse Event ..................................................................................... 14 
8.1.4 
Unexpected Adverse Drug Reaction (ADR) ............................................................. 14 
8.2 
Assessment of an Adverse Event ......................................................................................... 14 
8.2.1 
Relationship (Causality/Relatedness) ..................................................................... 14 
8.2.2 
Expectedness........................................................................................................... 14 
8.2.3 
Seriousness ............................................................................................................. 14 
8.2.4 
Severity.................................................................................................................... 15 
8.3 
Adverse Event Recording ..................................................................................................... 15 
8.4 
Reporting of SAEs and Unanticipated Events ...................................................................... 15 
8.4.1 
Investigator reporting: Notifying the REB ............................................................... 15 
8.4.2 
Investigator reporting: Notifying the Sponsor ........................................................ 16 
8.4.3 
Sponsor Reporting of SUADRs: Notifying Health Canada ....................................... 16 
8.5 
Type and Duration of Follow-up for Adverse Events ........................................................... 16 
8.6 
Reporting and Entry Timelines ............................................................................................. 16 
9 
SITE MONITORING, AUDITING AND INSPECTING ....................................................................... 18 
9.1 
Site Monitoring Plan ................................................................................................... 18 
9.2 
Auditing and Inspecting .............................................................................................. 18 
10 
STATISTICAL CONSIDERATIONS ................................................................................................ 19 
10.1 
Study Hypotheses ....................................................................................................... 19 
10.2 
Sample Size Considerations ......................................................................................... 19 
10.3 
Planned Interim Analyses ............................................................................................ 19 
10.4 
Stopping Rules ........................................................................................................... 19 
10.5 
Final Analysis Plan ...................................................................................................... 19 
10.5.1 PK modeling and development of dosing strategy ............................................ 19 
10.5.2 Statistics ........................................................................................................ 20 
11 
DATA HANDLING AND RECORD KEEPING .................................................................................. 21 
11.1 
Confidentiality ............................................................................................................ 21 
11.2 
Source Documents ..................................................................................................... 21 
11.3 
Data Management Responsibilities .............................................................................. 22 
11.4 
Data Capture .............................................................................................................. 22 
11.4.1 Case Report Forms ......................................................................................... 22 
11.5 
Records Retention ...................................................................................................... 22 
11.6 
Clinical Trial Registration ............................................................................................. 23 
12 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................................................... 24 
13 
ETHICS CONSIDERATIONS ........................................................................................................ 25 
13.1 
Ethical Standard ......................................................................................................... 25 
13.2 
Research Ethics Board (REB) ........................................................................................ 25 
13.3 
Consent ..................................................................................................................... 25 
14 
LITERATURE REFERENCES ........................................................................................................ 27 

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APPENDICES ....................................................................................................................................................  
APPENDIX A: SCHEDULE OF EVENTS ........................................................................................................... 29 
 

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LIST OF ABBREVIATIONS 
The following abbreviations describe terms, documents and study personnel used in the 
conduct of this study protocol. 
AE 
Adverse Event/Adverse Experience 
CC 
Coordinating Centre 
CIOMS 
Council for international Organizations of Medical Sciences 
CKD 
Chronic Kidney Disease 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CCTS 
Centre for Clinical Trial Support 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
EC 
Ethics Committee 
eGFR 
Estimated Glomerular Filtration Rate 
GFR 
Glomerular Filtration Rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IP 
Investigational Product 
DSMB 
Data and Safety Monitoring Board 
GCP 
Good Clinical Practice 
MedDRA 
Medical Dictionary for Regulatory Authorities 
pCRF 
Paper Case Report Form 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PM 
Product Monograph 
QI 
Qualified Investigator 
REB 
Research Ethics Board 
RCT 
Randomized Controlled Trial 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SHSC 
Sunnybrook Health Sciences Centre 
SOP 
Standard Operating Procedure 
SRI 
Sunnybrook Research Institute 

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SUADR 
Serious and Unexpected Adverse Drug Reaction 
TMF 
Trial Master File 
TXA 
Tranexamic Acid 
 
 
 

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PROTOCOL SUMMARY 
Protocol Title (Short 
Title) 
Tranexamic acid dosing for major joint replacement surgery (TXA-
Dosing) 
Protocol Number 
1567 
Phase 
II 
Study Design 
Prospective cohort study conducted at Sunnybrook Health Sciences 
Centre (SHSC). 
This study will investigate the optimal TXA dose for hip and knee joint 
replacement surgery. 20 participants (10 in each group) will be 
included and stratified into two groups:  
 Group I: participants with glomerular filtration rate (GFR) < 60 
mL/min/1.73m2 (and dialysis) 
 Group II: participants with GFR ≥ 60 mL/min/1.73m2 
Participants will be given single intravenous bolus of TXA 20 mg/kg 
over 15 min after induction of spinal (or other regional technique) or 
general anesthesia as per standard of care. Blood samples will be 
drawn from an arterial or venous catheter line at following time 
points after induction of anesthesia: baseline/pre-TXA 
administration, 5 min, 15 min, 30 min, 1h, 1.5h, 3h, 6h+/-2 and 
12h+/-4 post-bolus. 
Study Duration 
2 years 
Setting 
Single-centre 
Sample Size 
20  
Main Inclusion 
Criteria 
(1) Adults > 18 years old 
(2) Elective unilateral hip or knee joint replacement. 
Primary Outcome(s): 
Measurement of serial blood plasma TXA concentration to build a 
Pharmacokinetic (PK) model and dosing regimens for patients within 
both groups 
Secondary 
Outcome(s): 
(1) Intraoperative blood loss and transfusion 
(2) % reduction in pre- and postoperative hemoglobin 

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(3) Postoperative creatinine, GFR and other plasma renal biomarkers 
(for e.g., NGAL, SUPAR, cystatin) 
(4) In-hospital mortality 
(5) Hospital length of stay 
Investigational 
Product and Planned 
Use 
After spinal (or other regional technique) or general anesthesia, a 
single intravenous bolus of TXA 20 mg/kg will be given (as per our 
standard of care) over 15 minutes. 
Statistical Analysis: 
Continuous variables will be summarized using median (interquartile 
range) and studied using a Mann Whitney U test. Categorical 
variables will be summarized using frequency (%) and studied using a 
Chi-square. These analyses will be performed using SAS v9.6 (US).  
 
 
 

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1 KEY ROLES AND CONTACT INFORMATION 
Regulatory Sponsor: 
Sunnybrook Research Institute (SRI) 
2075 Bayview Avenue 
Toronto, ON Canada M4N 3M5 
Principal Investigator:   
Dr. Angela Jerath  
Academic Research 
Organization: 
Centre for Clinical Trial Support, SRI 
2075 Bayview Avenue 
Toronto, ON Canada M4N 3M5 
 
 
 
 
 
 
 

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2 INTRODUCTION  
This study document is the protocol for research involving human participants.  This study is to 
be conducted according to Canadian and international standards, and in compliance with the 
protocol, the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice E6 (GCP), World Medical Association 
Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Participants, as 
well as applicable regulatory and institutional requirements and research policies.  
2.1 
Background  
 
Over 1.7 million hip and knee replacements are performed annually worldwide.1,2 Hip and 
knee arthroplasty is associated with high blood loss (500-1500ml) and transfusion rates (18-
22%).3,4 High blood loss in this older patient group causes postoperative anemia that may need 
blood transfusion which is associated with adverse immune and non-immune reactions including 
fluid overload, lung injury, sepsis and incompatibility issues.5,6 
 
 
Tranexamic acid (TXA) is a routinely used anti-fibrinolytic agent, which limits blood loss and 
transfusion requirements during joint replacement surgery. The routine use of TXA during 
surgery is recommended by the American Society of Orthopedic Surgeons, and the Hip and Knee 
Society.7,8 Furthermore, a recent large meta-analysis, including 129 trials and 10488 patients, 
showed that TXA administration reduced the need for a transfusion by 38%, in a variety of surgery 
types.9 However, there are currently no consensus guidelines regarding optimal TXA dosing for 
joint arthroplasty patients. Current TXA dosing practice is heterogeneous with most practitioners 
adopting regimens from trauma or previous clinical trials that use doses between 10-30 mg/kg.10–
12 However, these dosing regimens lack any supporting pharmacological evidence. In addition, 
TXA is cleared nearly 100% by glomerular filtration.13 Evidence has shown that TXA accumulates 
in patients with chronic kidney disease (CKD) in proportion to the severity of renal dysfunction.13–
15 TXA dosing must be adjusted for patient renal function in order to avoid potentially toxic high 
plasma concentrations that could precipitate seizures and thrombosis.15–19 
 
 
The main objective of this prospective observational study is to assess TXA blood 
concentrations in patients requiring major arthroplasty surgery with varied preoperative renal 
function. We will use this information to create new dosing guidelines for patients undergoing 
major arthroplasty surgery. 
 
2.2 
Clinical Data to Date 
Optimal TXA dosing that maximizes the anti-fibrinolytic effect of TXA while avoiding toxic plasma 
concentration levels has been determined for cardiac surgery patients.15 These studies built TXA 
pharmacokinetic (PK) models in patients with varying levels of renal dysfunction using population 
PK modeling, a powerful statistical method used by drug regulatory bodies to establish safe 
human dosing regimens.20 This information was then used to develop new dosing regimens by 

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comparing PK data to older studies that showed plasma TXA levels around 100 mg/L provides 
near 100% anti-fibrinolytic activity.15 Similar studies are absent for major joint replacement 
surgery. A separate study is required in this surgical population because of differences in fluid 
shifts and the lack of cardiopulmonary bypass. 
2.3 
Potential Risks/Benefits and Rationale 
A total of 20 adult patients (>18 years of age) undergoing unilateral hip or knee replacement 
surgery will be included in this study. As all patients will be receiving standard of care treatment, 
we do not anticipate any additional risks to patients who participate in the study, beyond those 
normally associated with a surgery of this type. Only extra blood sampling will be required of a 
total volume of 30-50 ml.   

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3 STUDY OBJECTIVES 
3.1 
Primary Objective 
Determine optimal TXA dose for patients undergoing hip and knee joint replacement surgery, 
with or without CKD. 
3.2 
Secondary Objective(s) 
1. Develop a PK model and dosing regimen for major joint replacement surgery. 
2. Study metabolomic profile of patients undergoing joint arthroplasty.  
 
 
 

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4 STUDY DESIGN 
4.1 General Design 
Our study follows a prospective cohort study design without randomization or blinding. 20 
patients undergoing unilateral hip or knee replacement will be recruited and stratified into 2 
groups (each with 10 patients) with either glomerular filtration rate (GFR) < 60 mL/min/1.73m2 
(and dialysis) or GFR ≥ 60 mL/min/1.73m2. This GFR cut-off was chosen based on previous data 
showing low variability at GFR below and above 60, and plasma TXA levels differed due to 
reduction in TXA clearance rates between patients in each group.15  
 
After spinal/regional or general anesthesia, a single intravenous bolus of 20 mg/kg TXA will be 
administered (as per our standard of care) over 15 minutes. Serial 4-5 ml blood samples will be 
drawn at: baseline/pre-TXA administration, 5 min, 15 min, 30 min, 1h, 1.5h, 3h, 6h+/-2 and 
12h+/-4 post-bolus. These time points capture 2-3 TXA half-lives14, including peak and end of 
surgery (average 2 h) concentrations.  
 
Each blood sample will be collected into standard citrate collection tubes. Tubes will be inverted 
a minimum of 5 times to ensure proper mixing with anti-coagulant (sodium citrate). Each sample 
will be labeled with an anonymized patient study number (to de-identify patient information) 
and sample time. The tubes will be stored on ice bath following sample collection and then 
centrifuged within 2 hours at 2000g for about 15 min at 4˚C. The subsequent supernatant will be 
frozen and stored at -70˚C until analyzed. Measurement of TXA and other drug concentrations, 
renal biomarkers and metabolomics will be performed using liquid chromatography-tandem 
mass spectroscopy (LC-MS/MS) using previously described methodology.15 Patients will 
otherwise receive routine perioperative care. Patient follow up will be to hospital discharge. Our 
approach is consistent with several previous studies in this area. 15,21 
 
All samples will be collected at SHSC (Holland Orthopaedic Arthritic Centre). Sample analysis and 
pharmacokinetic modeling will be performed at the Department of Pharmacology, University of 
Toronto. No external sponsors are affiliated with this study. 
4.2 Primary Outcomes/Endpoint(s) 
Our primary outcome is the measurement of serial plasma TXA concentrations in order to build 
PK models and dosing regimens for both patient groups. i.e. participants with GFR < 60 
mL/min/1.73m2 (and dialysis) and participants with GFR ≥ 60 mL/min/1.73m2. 
4.3 Secondary Outcomes/Endpoint(s) 
We will report the following secondary outcomes:  
1. Intraoperative blood loss and transfusion 
2. % reduction in pre- and postoperative hemoglobin 

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3. Postoperative creatinine, GFR and other plasma renal biomarkers (e.g., NGAL, SUPAR, 
cystatin) 
4. In-hospital mortality 
5. Hospital length of stay 
4.4 Primary Safety Outcomes/Endpoints 
We do not anticipate any additional risks to participants associated with inclusion in this study. 
As such, no specific safety endpoints will be recorded. 
 

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5 PARTICIPANT SELECTION AND WITHDRAWAL   
5.1 
Inclusion Criteria 
Each participant must meet all of the following inclusion criteria to participate in this study: 
1. Adults > 18 years of age  
2. Elective unilateral hip or knee joint replacement  
5.2 
Exclusion Criteria 
All participants meeting any of the following exclusion criteria at baseline will be excluded from 
participation in this study:  
1. Contraindication to TXA (e.g., allergy, thrombophilia, tretinoin) 
2. Advanced liver disease (>2-fold rise in liver enzymes, as this may alter PK analysis) 
3. Anti-coagulant use within the last 1-4 days prior (depends on anticoagulant, prior to the 
day of surgery) 
5.3 
Participant Recruitment  
Patients considered suitable for study selection will be identified by study research staff from 
local surgical populations and confirmed by study investigators. Prospective participants will 
then be informed and invited to participate in the research study by their clinical team (i.e. 
team member who is part of circle of care). Participants will be approached by study staff prior 
to their surgery in order to gain informed consent. Participants will be informed about the 
purpose, procedures, benefits, risks, discomforts, and any precautions related to the study. The 
participant will be given enough time to read and ask questions about the study. Participants 
will be considered enrolled in the study after granting informed consent. 
No randomization or blinding procedures will be employed in this study, as all patients will 
receive the standard treatment. Patients will be stratified into two groups based on their GFR: 
Group 1: GFR < 60 mL/min/1.73m2 
Group 2: GFR ≥ 60 mL/min/1.73m2 

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5.4 
Participant Withdrawal and Discontinuation of IP 
5.4.1 
Reasons for Withdrawal/Discontinuation of IP 
Participants, or their substitute decision-maker, may withdraw from the study at any time and 
for any reason at their own discretion. Study participants may also be withdrawn from the 
study at the discretion of an investigator for reasons including, but not limited to patient safety.  
5.4.2 
Data Collection and Follow-up for Withdrawn Participants 
In the event of patient withdrawal from the study, no further study procedures or evaluations 
will be performed or additional study data collected for that patient. Data collected prior to the 
withdrawal of consent will be included in the analysis.  Every effort will be made to obtain 
permission to document the reason for withdrawal and to collect participant outcomes (e.g., 
survival data, any unresolved adverse events). Any relevant adverse events identified will be 
reported as per REB and Health Canada regulations. 

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6 INTERVENTIONS  
6.1 
Investigational Product  
TXA is a routinely used, Health Canada approved, anti-fibrinolytic agent, frequently used to 
reduce blood loss during major surgery. The trial involves investigating the off-label use of TXA. 
A Health Canada approval (‘No objection letter’) will be obtained prior to initiating a trial.  
6.1.1 
Acquisition, Formulation and Packaging 
6.1.1.1 
Acquisition and Formulation 
TXA is routinely administered to this patient population. We will be using our standard 
commercial stock (manufacturers SteriMax, Sandoz, Omega, Pfizer; as per institutional 
preference and directives as it will be used as part of clinical supply). The drug is stored at room 
temperature as a clear and colorless liquid. Standard concentration is 100 mg/ml. 
6.1.1.2 
Packaging 
TXA is stored in glass vials. It is routinely kept in anesthesia drug carts. This drug is a standard of 
care for routine hip and knee replacement surgery, and thus is not an investigational product. 
This study aims to observe the plasma concentrations that our standard doses achieve. 
6.1.2 
Treatment Assignment Procedures 
All consented study participants will be given the investigational product. Participants will be 
stratified to one of two groups based on kidney function/GFR.  
6.1.3 
Dosage, Preparation and Administration  
Following administration of spinal/regional or general anesthesia, a single bolus dose of TXA (20 
mg/kg) will be given intravenously to all study participants over 15 minutes, as per standard of 
care. See product monograph for detailed preparation and administration instructions. 
6.1.4 
Dose Modification  
The dose used is a standard clinical dose administered to all patients without modification.  
6.1.5 
Receiving, Storage, Dispensing and Return 
6.1.5.1 
Receipt of Investigational Product 
 
The investigational product (IP) is supplied by the hospital as per the institutional directives.  
Which IP is supplied is based on institutional preference as it will be used as part of clinical 
supply.  

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6.1.5.2 
Storage and Stability 
TXA should be stored at room temperature (15-30˚C) in the Pharmacy department. 
6.1.5.3 
Dispensing and Destruction of Investigational Product 
The investigational product will be reconciled and destroyed by the pharmacy team as per the 
institutional directives.  
6.1.6 
Prior and Concomitant Medications/Treatments 
 
We will collect the following preoperative information using medical history interview and 
medical record review: 
 Aspirin 
 Heparin 
 LMWT heparin 
 Plavix 
 Other anti-platelet (clopidogrel) 
 Other medications such as anti-hypertensives, diabetic medications. 
 

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7 STUDY SCHEDULE AND PROCEDURES 
All research procedures and interventions will be conducted during the initial hospitalization 
involving the participant’s surgery. Follow up will extend to hospital discharge. 
7.1 
Screening 
Eligible participants will be identified by research personnel from existing hospital surgical 
populations and confirmed by study investigators according to previously described 
inclusion/exclusion criteria. 
7.2 
Baseline/Enrollment 
Eligible individuals will be approached for informed consent prior to their surgery by 
appropriate research personnel. Individuals who give informed consent will be enrolled into the 
study. A baseline/pre-TXA blood sample will be taken prior to administration of the study 
intervention and used to stratify individuals into one of the two previously described groups 
according to their GFR. 
7.3 
Study visits 
Following administration of the study intervention (i.e. 20 mg/kg TXA IV bolus), blood samples 
will be drawn after 5 min, 15 min, 30 min, 1h, 1.5h, 3h, 6h+/-2 and 12h+/-4 post-bolus. No 
additional patient interaction/study visits will be required.  
Additional information relevant to the study will also be collected from patient medical records. 
This includes: 
 
Patient demographics 
 
Medical co-morbidities 
 
Medications 
 
Type and duration of surgery 
 
Blood transfusion/products 
 
Postoperative blood loss 
 
Laboratory tests (HB, PLT, Creatinine, INR, aPTT, eGFR)  
 
7.4 
Follow up 
No follow ups requiring patient interaction will be required. Patient follow up will take the form 
of chart review only and extend only to the point of hospital discharge. 
7.5 
Protocol Deviations 
It is the responsibility of the investigator to ensure that only investigative procedures, as 
outlined in this protocol are performed on study participants; the occurrence of deviations from 
the protocol or SOPs are limited; and compliance with the regulations is maintained.  Planned 

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deviations from the protocol must not be implemented without prior agreement from the 
sponsor and approval from the local REB/ethics committee (EC), as required, unless to 
eliminate an immediate hazard to a participant.  
Planned or unplanned deviations may occur on the part of the participant, the investigator, or 
study research team. In resolution to a deviation, corrective/preventative actions are to be 
developed and implemented in a timely manner. Protocol deviations will be documented and 
reported as required and assessed where necessary during analysis. 
 
 
 

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8 ASSESSMENT OF SAFETY 
The safety of research participants is foremost and should always be considered throughout the 
conduct of research.  
8.1 
Definitions 
8.1.1 
Adverse Events 
An adverse event (AE) means any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment, and includes an adverse drug 
reaction (ADR). 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
8.1.2 
Serious Adverse Events 
A serious adverse event (SAE) or reaction is any untoward occurrence that at any dose: 
 Results in death, 
 Is life-threatening, 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
 Results in persistent or in significant disability/incapacity, 
 Is a congenital abnormality or a birth defect. 
 
The term "life-threatening" in the definition of "serious" refers to an event in which the 
participant was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.  
 
Expected Serious Adverse Reactions according to the product monographs (SteriMax, Sandoz, 
Omega, Pfizer) include: 
 Gastrointestinal disorders: gastrointestinal symptoms (nausea, vomiting, diarrhea) occur 
but disappear when the dose is reduced  
 Nervous system disorders: dizziness, reduced blood pressure, seizures. 
 Immune system disorders: allergic dermatitis, anaphylaxis or anaphylactoid reaction 
 Eye disorders: impaired vision, blurred vision or colour vision impairment 
(chromatopsia) 
 Vascular disorders: thromboembolic events (acute myocardial infarction, thrombosis, 
arterial thrombosis limb, carotid artery thrombosis, cerebral infarction, cerebrovascular 
accident, deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal 

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cortical necrosis, and central retinal artery and vein obstruction). Hypotension may 
occur after fast injection. 
 
8.1.3 
Unexpected Adverse Event 
An unexpected adverse event is any AE that is not identified in nature, severity or frequency in 
the current Investigator’s Brochure or Product Monograph. 
8.1.4 
Unexpected Adverse Drug Reaction (ADR) 
An ADR is an adverse reaction, the severity of which is not consistent with the applicable 
Investigator’s Brochure or Product Monograph.   All noxious and unintended responses to a 
medicinal product related to any dose should be considered an ADR.  
The phrase "responses to a medicinal product" means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out.  
The expression “causal relationship” is meant to convey that in general there are facts, 
evidence or arguments to suggest a reasonable causal relationship.  All serious and unexpected 
ADRs will have expedited reporting to regulatory agencies following ICH-GCP and local 
regulatory requirements. 
8.2 
Assessment of an Adverse Event 
8.2.1 
Relationship (Causality/Relatedness) 
The causality assessment is the determination, according to the investigator’s clinical judgment, 
of the existence of a reasonable possibility that the study drug (IP) caused or contributed to an 
adverse event.  
If the investigator or delegated sub-investigator is unsure about whether or not the study drug 
caused or is related to the event, then the event will be handled as “related” to the study drug 
for reporting purposes of the trial.  If the causality assessment is "unknown but not related” to 
the study drug, this should be clearly documented in the source documents.  
8.2.2 
Expectedness  
Events are classified as unforeseen or unexpected if the nature, severity or frequency is not 
consistent with the risk information set out in the Product Monograph (PM) or label.     
8.2.3 
Seriousness 
Events are classified as serious if associated with effects threatening the life or physiological 
functions of a participant.  Refer to the definition for “Serious Adverse Events” in section 8.1.2. 

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8.2.4 
Severity  
The term "severe" is often used to describe the intensity (severity) of a specific event (e.g. mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as severe headache). This is not the same as "serious," which is 
based on participant/event outcome or action criteria usually associated with events that pose 
a threat to a participant's life or functioning. The terms “serious” and “severe” are not 
synonymous.  Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
8.3 
Adverse Event Recording 
 
Investigations into potential adverse events should be done during each contact with a 
participant.  Investigations may be done through specific questioning and, as appropriate, by 
examination.  Information on all adverse events should be recorded promptly in the source 
document, and assessed by an investigator in a timely manner allowing sufficient time to meet 
required reporting timelines for SAEs and SUADRs if needed.  Adverse event CRFs should be 
completed using source documents by a delegated research team member in a timely 
manner/within 15 days of site awareness.  All clearly related signs, symptoms, and abnormal 
diagnostic procedures should be recorded in the source document, though should be grouped 
under one diagnosis.  
 
Adverse Events that are determined by the Investigator to be definitely, probably, or possibly 
related to the study drug(s) will be recorded. Adverse events that are assessed and determined 
unrelated or unlikely related to the investigational product will not be recorded and reported. 
The following are not considered AEs and therefore do not require recording:  
 Pre-existing diseases or conditions identified and recorded at screening/baseline unless, 
at the discretion of the investigator, the disease or condition worsens in severity or 
frequency  
 At the discretion of the investigator, events considered likely manifestations of the 
underlying disease or that commonly occur in the study population independent of IP 
exposure 
 Elective medical or surgical procedures.   
8.4 
Reporting of SAEs and Unanticipated Events 
8.4.1 
Investigator reporting: Notifying the REB 
 
 

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Serious adverse events and unanticipated events should be recorded and reported to the REB 
in accordance with local reporting requirements and timelines.    
8.4.2 
Investigator reporting: Notifying the Sponsor 
 
The investigator is responsible for reporting serious adverse events and serious and unexpected 
adverse drug reactions (SUADRs) to the sponsor in accordance with applicable regulations and 
reporting requirements and timelines.    
 
Events that are assessed to be serious and unexpected and related or cannot be ruled out as 
related to the investigational product are considered SUADRs.  Reporting for SUADRs should 
include a description of the event in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality.  The minimum 
information required includes at least one identifiable participant, one identifiable reporter, 
one serious reaction, and one suspect product.  
 
Additionally, a Suspect Adverse Reaction Report – CIOMS I Form must be completed by the 
investigator and forwarded to the Sponsor within 24 hours of site awareness.  Information on 
other possible causes of the event, such as concomitant medications and illnesses should also 
be provided as soon as is made available. 
8.4.3 
Sponsor Reporting of SUADRs: Notifying Health Canada 
 
The regulatory sponsor is responsible for reporting SUADRs to regulatory authorities in 
accordance with local expedited reporting requirements and timelines.  In addition, the 
Sponsor will complete the ADR Expedited Reporting Summary Form and submit this form in 
conjunction with the completed CIOMS Form to the appropriate Health Canada directorate.    
8.5 
Type and Duration of Follow-up for Adverse Events  
 
AEs occurring as of the first administered dose of the investigational product and until hospital 
discharge will be collected.  AEs recorded during this period will be followed through to 
resolution, or until the event is assessed as chronic or stable. 
8.6 
Reporting and Entry Timelines 
 Study investigators will report SAEs to the sponsor within the following timelines:   
 All deaths and immediately life-threatening events, whether related or unrelated, 
will be recorded and reported to the sponsor within 24 hours of site awareness.  
 Serious adverse events other than death and immediately life-threatening events, 
regardless of relationship, will be reported to the sponsor within 72 hours of site 
awareness.  
 

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Adverse event information will be entered into the CRF in a timely manner and no later than 15 
days from the time the investigator becomes aware of the event. 
 
Serious adverse event information will be entered into the CRF in a timely manner/within 72 
hours from the time the investigator becomes aware of the event. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9 SITE MONITORING, AUDITING AND INSPECTING 
9.1 
Site Monitoring Plan 
 
Site monitoring is conducted to ensure the safety of human study participants and the protection 
of their rights and well-being.  Monitoring also verifies that collected study data is accurate, 
complete and verifiable by source documentation and that the study is conducted in accordance 
with the protocol and operating procedures. 
Monitoring for this study is the responsibility of the sponsor.  The delegated monitor will 
evaluate study processes and documentation based on the approved protocol/amendment(s), 
Part C, Division 5 of the Food and Drug Regulations, the International  Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), E6: Good 
Clinical Practice guidelines (GCP) and institutional policies. 
The extent and nature of monitoring is outlined in the Monitoring Plan. The monitoring plan 
specifies the frequency of monitoring, monitoring procedures, the level of site monitoring 
activities (e.g., the percentage of participant data to be reviewed), and the distribution of 
monitoring reports.  Monitoring activities will be performed both in person and remotely.  
Reports of findings identified during monitoring activities will be provided to sites detailing any 
required actions.  Documentation of monitoring activities and findings will be provided to the 
site study team and the study QI. The institution and/or local REB reserves the right to conduct 
independent audits as necessary. 
The Investigator is responsible for ensuring monitors and/or quality assurance reviewers are 
given access to all study-related documents noted above and study related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.), and have adequate space to conduct the monitoring 
visit or audit. 
9.2 
 Auditing and Inspecting 
 
The investigator will provide direct access to source data/documents for the purposes of study-
related monitoring, audits, and inspections by the REB, the sponsor, and applicable regulatory 
bodies.  The investigator will permit the review of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.) and will ensure 
access to applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 

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10 STATISTICAL CONSIDERATIONS 
10.1 
Study Hypotheses 
Current TXA dosing procedures result in suboptimal plasma TXA concentrations. 
10.2 
Sample Size Considerations 
Using a 2-tailed unpaired t-test with a significance α-level of 0.05, power of 80%, expected 
mean difference in TXA clearance of 0.0275 L/h/kg and standard deviation for all subjects of 
0.044 L/h/kg (based on previous TXA studies in patients with different CKD stages) a total 
sample size of 20 patients (10 per group) is required.13 
10.3 
Planned Interim Analyses  
No interim analyses will be performed. 
10.4 
Stopping Rules 
This study will be stopped prior to its completion if:  
a) The intervention is associated with adverse events that call into question the safety of the 
intervention. 
b) Difficulty in study recruitment or retention will significantly impact the ability to evaluate the 
study endpoints. 
c) Any new information becomes available during the trial that necessitates stopping the trial. 
 
As per protocol section 7.3,  following administration of the study intervention (i.e. 20 mg/kg 
TXA IV bolus), blood samples will be drawn after 5 min, 15 min, 30 min, 1h, 1.5h, 3h, 6h+/-2 
and 12h+/-4 post-bolus. No additional patient interaction/study visits will be required, and we 
do not expect subjects to be withdrawn or replaced. The IP is being used in an observational 
study only as per standard hospital guidelines. If however, there is any adverse reaction to the 
IP, the standard internal hospital protocols will apply regrading monitoring the patient and 
treatment as appropriate to the reaction, plus notification of the adverse event. 
 
10.5 
Final Analysis Plan 
10.5.1 PK modeling and development of dosing strategy 
We will build 2 PK profiles for patients with GFR < 60 and with GFR ≥ 60 mL/min/1.73m2. We will 
determine clearance, volume of distribution, and inter-compartment rate constants using a 2-
compartment model with mass balance equations.15,21 NOMEM® 7.2.0 (non-linear mixed effects 
modeling, ICON Development Solutions, US) and ADAPT5 (D’Argenio, US) will be used for data 
fitting and population-PK analyses. Population-PK modeling will involve identification of 

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measurable source of variability and the relationship between PK and the pathological conditions 
(e.g. renal function), which are essential for dose optimization. Pathophysiological factors (e.g., 
body weight, creatinine clearance) that could explain the inter-subject variability will also be 
explored. The unexplained (random) variability in patient population will also be quantified.  
 
The ratio of the steady state concentration to the therapeutic plasma concentration of 100 mg/L 
which provides near 100% inhibition of fibrinolytic activity, will be compared to guide the dose 
adjustment correction factor. 
10.5.2 Statistics 
Continuous variables will be summarized using median (interquartile range) and assessed using 
the Mann-Whitney U test. Categorical variables will be summarized using frequency (%) and 
assessed using a Chi-square test. These analyses will be performed using SAS v9.6 (US).  
 

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11 DATA HANDLING AND RECORD KEEPING 
11.1 Confidentiality 
Information about study participants will be kept confidential and managed according to the 
requirements of the Personal Health Information Protection Act of 2004 (PHIPA) and the 
Research Ethics Board.  PHIPA outlines the rules for the collection, use and disclosure of 
personal health information.  The Act requires each participant to consent to the collection, use 
and access of personal health information (PHI), unless consent is waived by the REB.  Where 
consent is required, each participant must be informed of the following:  
 
 What PHI will be collected during this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research participant to revoke their authorization for use of their PHI.  
 
In the event that a participant revokes authorization to collect or use PHI, the investigator may 
use all information collected prior to the revocation of participant authorization.  For 
participants that have revoked authorization to collect or use PHI, attempts should be made to 
obtain permission to collect at least vital status (i.e. that the participant is alive) at the end of 
their scheduled study period. 
11.2 Source Documents 
Source data/documents are original documents, data and records in a clinical study that are 
necessary for the reconstruction and evaluation of the study.  Examples of these original 
documents and data records include, but are not limited to: 
 Worksheets 
 hospital records  
 medical records 
 memorandum  
 participants’ diaries or evaluation checklists  
 pharmacy dispensing records  
 recorded data from automated instruments (i.e. ECGs) 
 copies or transcriptions certified after verification as being accurate and complete  
 participant files and records kept at the pharmacy  
 entries entered directly into the printed CRF 
 
We will maintain appropriate medical and research records for this study, in addition to 
regulatory and institutional requirements for the protection of confidentiality of participants.  If 

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electronic source data documents is printed it should be signed and dated by the investigator to 
confirm content and filed with other source documents.  
The investigator(s) and research team members listed on the Task Delegation Log (TDL) will 
have access to participant medical records and will collect only the information needed for the 
study.  Sponsor delegated monitors, representatives of institutional committees and regulatory 
authority representatives of the country in which the study is being conducted will also have 
access to examine records for the purposes of quality assurance reviews, audits and evaluation 
of study safety and progress. 
 
11.3 Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study personnel under 
the supervision of the investigator.  All source documents and applicable laboratory reports 
should be reviewed as needed and used to ensure that data collected for the purposes of the 
study are accurate and complete.  Contemporaneous review of laboratory results and the 
assessment of clinical significance for those results considered out of range should be 
documented by means of dated signature by the reviewing investigator. Study personnel, 
including data entry team members, should use source documents to complete case report 
forms (CRFs).  
As part of the safety plan for this study, the investigator will review individual study participant 
records to ensure that appropriate mechanisms to protect the safety of study participants are 
being followed, that protocol requirements are being adhered to, and that data is accurate, 
complete, and secure. Participant records include, but are not limited to: consent forms, case 
report forms, data forms, laboratory specimen records, inclusion/exclusion forms, and medical 
charts. All study data will be collected by a member of the study research team and recorded in 
accordance with applicable procedures. 
 
11.4 Data Capture 
11.4.1 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  Paper 
case report forms (pCRFs) will be used to collect data for this study. pCRFs are to be completed 
by data capture personnel and signed off by the investigator in a timely manner.  Good 
documentation practices should be implemented according to standard operating procedures.  
All data requested on the pCRF must be recorded and verifiable by source documents.   
11.5 Records Retention 
It is the responsibility of the REB, investigator and regulatory sponsor to retain study essential 
documents as per local regulatory requirements and GCP Guidelines.   

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Study essential documents will be maintained in a secure and confidential manner for a period 
of 25 years.  For the purposes of this study, the start date of the retention period is the date of 
the final report of the trial. All study records are then to be destroyed according to local and 
national policy and requirements. It is the investigator’s responsibility to request authorization 
for destruction at the completion of the retention period. 
11.6 Clinical Trial Registration 
In accordance with Health Canada’s Notice “Registration and Disclosure of Clinical Trial 
Information, November 30, 2007”, the sponsor will be responsible for registering the study on 
Clinicaltrials.gov (www.clinicaltrials.gov), a publicly available registry that conforms to 
international standards for registries. 

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12 QUALITY CONTROL AND QUALITY ASSURANCE 
As per ICH-GCP and local regulations, the sponsor is responsible for ensuring the 
implementation and maintenance of systems that support quality assurance and quality 
control.  
The study must be conducted in compliance with the study protocol and all data collected must 
be accurate and verifiable by source document(s). For the purpose of monitoring and auditing 
by the Sponsor, and inspection by regulatory authorities, the site will provide direct access to all 
study related source data/documents. The sponsor will verify that the study is conducted and 
data has been collected, documented (recorded), and reported in compliance with the 
protocol, GCP, and applicable regulatory requirements.  
Data for the study will be centrally stored and managed by the Centre for Clinical Trial Support 
(CCTS) at SHSC. To ensure the quality of study data, quality assurance and control systems will 
be implemented using validated electronic quality control checks within the electronic data 
capture system.  These verification measures will identify missing data, inconsistencies and/or 
data anomalies.  Both electronic and manual queries will be generated for resolution and 
review.   
Access to secure and validated electronic systems used for the purposes of this study will be 
controlled by the sponsor.  Access will only be granted to individual research team members 
upon review of training and qualification and authorization by delegation of the investigator.   
Quality assurance and control measures will be implemented to ensure training for specific 
trial–related tasks beyond the usual scope of practice.  Only procedures or interventions as 
outlined in Section 7, are considered study specific procedures requiring additional training, 
and will be reviewed for documentation of training and/or qualification.  
 

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13 ETHICS CONSIDERATIONS 
13.1 
Ethical Standard 
The investigator will ensure that this study is conducted in accordance with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Participants of Research, and codified in the Tri-Council Policy Statement and/or the ICH E6.  
13.2 
Research Ethics Board (REB)  
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the REB for review and approval.  Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled.  Any amendment to the 
protocol will require review and approval by the REB before the changes are implemented in 
the study, unless to eliminate an immediate hazard.   
13.3 
Consent  
Informed consent is a process that is initiated prior to the individual agreeing to participate in 
the study and continues throughout study participation. A consent form describing in detail the 
study procedures and risks will be reviewed with and given to each participant. Consent forms 
will be REB-approved, and the participant is required to read and review the document or have 
the document read to him or her. The investigator or designee will explain the research study 
to the participant and answer any questions that may arise. The participant will sign the 
informed consent document prior to any study-related assessments or procedures. Participants 
will be given the opportunity to discuss the study with their surrogates or think about it prior to 
agreeing to participate. They may withdraw consent at any time throughout the course of the 
study.  A copy of the signed informed consent document will be given to participants for their 
records.   
Prior to involvement in any study-related activities, consent must be obtained in writing for 
each participant using the current REB approved informed consent from. It is the responsibility 
of the investigator to ensure that all advertisements and written information, including the 
informed consent form, disseminated to participants has been approved by the local REB prior 
to use. The ethics approved Informed Consent Form (ICF) and any other written information, 
must be provided to each participant, allowing ample time to ask and have answered any 
questions prior to making a decision regarding participation. Neither the investigator nor study 
staff should unduly influence or coerce a participant to participate in the study.   
The ICF will be signed and dated by the participant and individual obtaining consent. The 
consent process will be documented in the clinical or research record.   
The original ICF, in its entirety, will be maintained by the site, and a complete copy of the signed 
ICF provided to the participant. The rights and welfare of the participants will be protected by 

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emphasizing to them that the quality of their clinical care will not be adversely affected if they 
decline to participate in this study. 
The provision of consent is an ongoing process and should be maintained throughout the 
duration of the study.  Participants may withdraw consent at any time throughout the course of 
the study. 

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APPENDIX A: SCHEDULE OF EVENTS 
 
 
 
Eligible Patients Enrolled 
(n=20) 
GFR < 60 mL/min/1.73m2 
(n=10) 
Baseline Blood Sample 
Administration of Intervention 
(20mg/kg TXA) 
Blood sampling at 5min, 15min, 
30min, 1h, 1.5h, 3h, 6h+/-2 and 
12h+/-4 post-bolus 
Laboratory Analysis and 
Patient Chart Review 
GFR ≥ 60 mL/min/1.73m2 
(n=10) 
Baseline Blood Sample 
Administration of Intervention 
(20mg/kg TXA) 
Blood sampling at 5min, 15min, 
30min, 1h, 1.5h, 3h, 6h+/-2 and 
12h+/-4 post-bolus 
Laboratory Analysis and 
Patient Chart Review