A Prospective, Randomized, Single-blinded Superiority Study to Evaluate Bone Wax Use for Hemostasis During Primary Unilateral Total Knee Arthroplasty
Phase: NA
Conditions: Total Knee Replacement
Sponsor: Northwell Health

 
A prospective, randomized, single-blinded superiority study to 
evaluate bone wax use for hemostasis during primary unilateral total 
knee arthroplasty 
 
 
 
Protocol Number:      21-0044 
National Clinical Trial (NCT) Identified Number:  NCT04992052 
Principal Investigator: Eugene S. Krauss, MD  
Version Number:  v.2.0 
         08Feb2022 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Cover 
Addition of NCT number 
 
 
 
 

  
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Table of Contents  
 
1. 
STATEMENT OF COMPLIANCE ................................................................................................................ 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 4 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 5 
2 
INTRODUCTION ............................................................................................................................................ 5 
2.1 
Study Rationale .................................................................................................................................... 5 
2.2 
Background........................................................................................................................................... 6 
2.3 
Risk/Benefit Assessment .................................................................................................................... 8 
2.3.1 
Known Potential Risks ..................................................................................................... 8 
2.3.2 
Known Potential Benefits ................................................................................................ 8 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 8 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 9 
4 
STUDY DESIGN ........................................................................................................................................... 10 
4.1 
Overall Design .................................................................................................................................... 10 
4.2 
Scientific Rationale for Study Design.............................................................................................. 11 
4.3 
Justification for Dose ......................................................................................................................... 12 
4.4 
End of Study Definition ..................................................................................................................... 12 
5 
STUDY POPULATION ................................................................................................................................ 13 
5.1 
Inclusion Criteria ................................................................................................................................ 13 
5.2 
Exclusion Criteria ............................................................................................................................... 13 
5.3 
Lifestyle Considerations .................................................................................................................... 14 
5.4 
Screen Failures .................................................................................................................................. 14 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 14 
6 
STUDY INTERVENTION ............................................................................................................................ 15 
6.1 
Study Intervention(s) Administration ............................................................................................... 15 
6.1.1 
Study Intervention Description ..................................................................................... 15 
6.1.2 
Dosing and Administration ............................................................................................ 15 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 16 
6.2.1 
Acquisition and accountability ...................................................................................... 16 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 16 
6.2.3 
Product Storage and Stability ....................................................................................... 16 
6.2.4 
Preparation ...................................................................................................................... 16 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 17 
6.4 
Study Intervention Compliance ........................................................................................................ 17 
6.5 
Concomitant Therapy ........................................................................................................................ 17 
6.5.1 
Rescue Medicine ............................................................................................................ 17 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 17 
7.1 
Discontinuation of Study Intervention ............................................................................................. 17 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 18 
7.3 
Lost to Follow-Up ............................................................................................................................... 18 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 18 
8.1 
Efficacy Assessments ....................................................................................................................... 18 
8.2 
Safety and Other Assessments ....................................................................................................... 19 

  
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8.3 
Adverse Events and Serious Adverse Events ............................................................................... 19 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 19 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 19 
▪ 
8.3.3 Classification of an Adverse Event .................................................................... 20 
8.3.3.1 
Severity of Event ................................................................. 20 
8.3.3.2 
Relationship to Study INTERVENTION ........................... 20 
8.3.3.3 
Expectedness ...................................................................... 21 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 21 
8.3.5 
Adverse Event Reporting .............................................................................................. 22 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 22 
8.3.7 
Reporting Events to Participants ................................................................................. 22 
8.3.8 
Events of Special Interest ............................................................................................. 22 
8.3.9 
Reporting of Pregnancy ................................................................................................ 22 
8.4 
Unanticipated Problems .................................................................................................................... 22 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 22 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 23 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 24 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 24 
o 
9.1 Statistical Hypotheses ................................................................................................................ 24 
9.2 
Sample Size Determination .............................................................................................................. 25 
9.3 
Populations for Analyses .................................................................................................................. 25 
9.4 
Statistical Analyses............................................................................................................................ 26 
9.4.1 
General Approach .......................................................................................................... 26 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 26 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 26 
9.4.4 
Safety Analyses .............................................................................................................. 26 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 26 
9.4.6 
Planned Interim Analyses ............................................................................................. 26 
9.4.7 
Sub-Group Analyses ..................................................................................................... 27 
9.4.8 
Tabulation of Individual participant Data .................................................................... 27 
9.4.9 
Exploratory Analyses ..................................................................................................... 27 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 27 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 27 
10.1.1 
Informed Consent Process ........................................................................................... 27 
10.1.1.1 
Consent/assent and Other Informational Documents 
Provided to participants ...................................................... 27 
10.1.1.2 
Consent Procedures and Documentation ....................... 27 
10.1.2 
Study Discontinuation and Closure ............................................................................. 28 
10.1.3 
Confidentiality and Privacy ........................................................................................... 28 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 29 
10.1.5 
Key Roles and Study Governance .............................................................................. 29 
10.1.6 
Safety Oversight ............................................................................................................. 29 
10.1.7 
Clinical Monitoring .......................................................................................................... 29 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 29 
10.1.9 
Data Handling and Record Keeping ............................................................................ 29 
10.1.9.1 
Data Collection and Management Responsibilities ....... 29 
10.1.9.2 
Study Records Retention ................................................... 30 

  
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10.1.10 
Protocol Deviations ........................................................................................................ 30 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 30 
10.1.12 
Conflict of Interest Policy .............................................................................................. 31 
10.2 
Additional Considerations-Appendix ............................................................................................... 31 
10.3 
Abbreviations ...................................................................................................................................... 32 
10.4 
Protocol Amendment History ........................................................................................................... 34 
11 
REFERENCES ............................................................................................................................................. 36 
 

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1. STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 
812)  
 
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the Institutional Review Board (IRB) 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 IRB before the changes are implemented to the study.  In addition, all 
changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
A prospective, randomized, single-blinded superiority study to 
evaluate  bone wax use for hemostasis during primary unilateral total 
knee arthroplasty  
Study Description: 
Total joint arthroplasty can result in significant blood loss.      
Postoperative anemia has      been associated with prolonged length 
of stay and increased hospital costs.1 Minimizing blood loss has led 
to multiple blood conservation strategies in orthopaedic procedures.   
Bone wax is a well-known topical hemostatic agent comprised of a 
mixture of beeswax, paraffin, and isopropyl palmitate.  This 
inexpensive agent works by sealing the bleeding site and tamponades 
bleeding from the cancellous bone.  Bone wax can be precisely 
applied evenly and stops bone bleeding immediately upon 
application.2       
 
The purpose of this study is to assess whether the application of bone 
wax to exposed cancellous bone, after the cemented implants are in 
place,  will provide superior hemostasis in total knee arthroplasty 
(TKA) patients compared to patients who do not have the bone wax 
applied.  Hemostasis will be assessed by calculating blood loss using 
the Hb-balance formula.   

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This will be a prospective, randomized, single-blinded, superiority 
study in patients scheduled for a primary unilateral TKA with Dr. 
Eugene Krauss or Dr. Ayal Segal.  The restriction of this study to 
two surgeons will limit variations in the outcomes being measured 
due to differences in surgical technique. 
 
Objectives: 
 
 
Primary Objective: 
 
• Efficacy: 
To assess whether bone wax results in superior hemostasis in 
patients undergoing primary unilateral TKA 
 
• Safety: 
To compare the safety profile between the 2 cohorts 
 
Secondary Objective: 
 
• To assess whether the objective and functional outcomes in 
patients undergoing primary unilateral TKA differ between 
the patient cohorts (use of bone wax vs no bone wax) 
 
• To assess if there is a difference in the reduction of the 
Hemaglobin (Hgb) and Hematocrit (Hct) between the patient 
cohorts 
 
Endpoints: 
Endpoints-Primary:  
● Efficacy: 
To calculate estimated perioperative blood loss on POD 1 
using the Hb-balance formula  
 
● Safety:  
To assess the patients for any device adverse events related to 
the use of bone wax 
 
 
 
Endpoints-Secondary:  
● To calculate the Knee Society Scores (KSS), both objective 
and subjective scores, done preoperatively and 8 weeks 
postoperatively  
 
● To measure the difference between the preoperative and 
POD1 Hemoglobin (Hgb) and Hematocrit(Hct) values in the 
two patient cohorts 
 

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Study Population: 
100 female and male patients (50 subjects in each arm) scheduled for 
unilateral total knee arthroplasty by Drs. Krauss or Segal 
 
Phase: 
NA 
Description of 
Sites/Facilities 
Enrolling Participants: 
 
Department of Orthopaedics, Syosset Hospital  
 
Description of Study 
Intervention: 
Bone wax is a well-known topical hemostatic agent comprised of a 
mixture of beeswax, paraffin, and isopropyl palmitate.  This 
inexpensive agent works by sealing the bleeding site and tamponades 
bleeding from the exposed cancellous bone.2       
 
Study Duration: 
The study timeline is 18 months 
 
Participant Duration: 
Patients will be in the study from the date of consent until their  
8 week postoperative visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.2 
SCHEMA 
 
 
 
 
 
 
 
Consent  
Preoperative Period 
 
Total n=100 (50 subjects in each arm) 
Preoperative Knee Society Score  
Obtain informed consent 
Collect Baseline Laboratory Values (Standard of Care) 
Screen potential participants by inclusion and exclusion criteria 
 
Randomization 
Day of Operation  
 
Confirm Inclusion/Exclusion Criteria 
Group 1-Bone Wax  (n=50) 
Group 2-No Bone Wax (n=50) 
Baseline assessments/ Study Intervention 
Hospitalization  
 
Complete Blood Count (CBC) (Standard of Care lab) 
Calculation of  
Device Adverse Event Assessment 
 
Follow-up assessments of study endpoints and safety 
Postoperative 8 week 
i it
 
 
 
           
Postoperative KSS  
 
Device Adverse Event Assessment  
Follow-up Telephone Call (Standard of Care) 
8 week follow-up phone 
ll
 
  

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
                                                         
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Total joint arthroplasty can result in significant blood loss. Bone wax is a well-known topical 
hemostatic agent comprised of a mixture of beeswax, paraffin, and isopropyl palmitate.  This 
inexpensive agent works by sealing the bleeding site and tamponades bleeding from the exposed 
cancellous bone. 2      
The purpose of this study is to assess whether the application of bone wax to the exposed 
cancellous bone, after the cemented implants are in place, will provide superior hemostasis in a 
total knee arthroplasty patients compared to patients who do not have the bone wax applied.  
Hemostasis will be assessed by calculating blood loss using the Hb-balance formula.         
This will be a prospective, randomized, single-blinded, superiority study in patients scheduled 
for a primary unilateral TKA with Dr. Eugene Krauss or Dr. Ayal Segal.  The restriction of this 
study to two surgeons will limit variations in the outcomes being measured due to differences 
in surgical technique.  The application of bone wax to the exposed cancellous bone has been 
the standard of care for four years by Drs. Krauss and Segal. The surgeons technique is to apply 
the bone wax to the exposed cancellous bone after the implant has been cemented in place 
thereby eliminating the risk for any issues with bone ingrowth.  

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2.2 
BACKGROUND  
 
     Postoperative anemia has also been associated with prolonged length of stay and increased 
hospital costs.1       In order to minimize blood loss, multiple blood conservation strategies have 
been developed for orthopaedic procedures.      One method of hemostasis in use at Syosset 
hospital since March 2013 is the use of intravenous antifibrinolytics (tranexamic acid). 
Tranexamic acid (TXA) interferes with clot breakdown. The  administration of tranexamic acid has 
been associated with a significant reduction of postoperative bleeding and blood transfusions in 
patients undergoing total joint arthroplasty and has become a well-established practice in 
orthopaedic surgery. Porter, et al in a 2020 retrospective chart review of 38,220 patients 
administered intravenous tranexamic acid (IV TXA) found no significant difference in the odds of 
adverse outcomes (PE,DVT, MI,CVA) between high-risk patients who received TXA and high-risk 
patients who did not receive TXA.  However, one of the limitations of the study was that high-
risk patients who did not receive TXA had a higher baseline incidence of risk factors such as 
DVT,PE, MI, and CVA compared to the high risk patients who did receive TXA.3 This manuscript 
was the basis for the current departmental protocol for the administration of TXA. As per this 
protocol IV TXA  is typically not administered to patients with multiple risk factors for 
thromboembolic events and they are instead given intra-articular TXA by the orthopaedic 
surgeon  Patients excluded from IV TXA will not be enrolled in this clinical trial so as to eliminate 
any confounding factors.      (Appendix A-Total Joint Arthroplasty Pharmacologic Protocols)      
      
Epidural or spinal anesthesia (neuraxial blockade) has been shown to be effective in reducing 
intraoperative blood loss. Rodgers, et al in a meta-analysis of 473 patients in 16 trials reported 
the requirement for a transfusion of two or more units of blood was reduced by about half in 
patients allocated to neuraxial blockade.4      Spinal or epidural anesthesia causes a sympathetic 
nerve block leading to vasodilatation distal to the site of anesthesia this effect is responsible for 
the reduction in bleeding during surgery.  
      
Another method used intraoperatively to maintain hemostasis is the application of a pneumatic 
tourniquet. During TKA, a pneumatic tourniquet is applied to the upper part of the thigh on the 
operative limb and inflated to a pressure determined by the surgeon. The tourniquet applies 
pressure to the limb to occlude the blood supply. The tourniquet is released by the surgeon at 
the end of the case and electrocautery is then used to seal any bleeding vessels.  
 
Significant blood loss intraoperatively and post-operatively can produce complications. The use 
of hemostatic agents such as bone wax may further facilitate hemostasis during a total knee 
arthroplasty. Bone wax was developed in 1885 by a British neurosurgeon named Sir Victor 

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Horsley. Bone wax consists of beeswax, paraffin and isopropyl palmitate. Since its first 
documentation of hemostatic potential in 1892, there has been a number of modifications to its 
formulation.2  The main component that remains is beeswax. Today bone wax is used in a variety 
of surgical procedures as a mechanical hemostatic agent. During total joint arthroplasties bone 
wax is softened and applied firmly on the cancellous bone around the prostheses. 
 
Bone wax increases hemostasis because of its ability to immediately seal and plug marrow 
sinusoid and consequently prevent oozing of blood.3 Studies have shown other benefits of bone 
wax, like the ability to decrease post-operative edema and pain.5       In the study conducted by 
Moo et al. 100 patients were recruited into a 1:1 randomization: (1) bone wax (2) control. 
Measurements were taken for height, weight, serum hemoglobin levels and base line lower limb 
diameters. Hemoglobin (Hgb) and Hematocrit (Hct) levels were checked on POD 1 and POD 3. 
Each study subject underwent total knee arthroplasty using standard procedures. Bone wax was 
applied around the prosthesis to obtain hemostasis in these areas. A significant decrease in blood 
loss was observed in the bone wax group at POD 1 and 3. None of the patients in the bone wax 
cohort required blood transfusions. Three patients in the control group required a blood 
transfusion.2      
 
The limitations in the Moo et al. study were, they did not collect postoperative outcomes such as 
pain, range of motion, and Knee Society Score (KSS).  Efficacy and safety data are lacking in this 
publication as most patients were transferred to a rehabilitation facility. Long term follow-up on 
clinical outcomes such as range of motion and functional assessment scores were not reported. 
The study subjects consisted of patients with osteoarthritis of the knee only, thereby, excluding 
whether patients with other inflammatory arthritis may benefit from the use of bone wax. The 
use of a chemical hemostatic agent tranexamic acid (TXA) was also excluded from the surgical 
procedure. The incorporation of TXA could have increased the level of hemostasis.    
 
A recently published manuscript by Shin, et al also evaluated blood loss outcomes with the use 
of bone wax.  Though this study also found bone wax reduced blood loss there were several 
limitations to the study.  First, its retrospective design is inherently disadvantageous.  Second, 
the postoperative outcomes such as pain score, range of motion, length of stay and clinical 
scores, were not comparted between the groups. Third, although there was no significant 
intergroup difference in the radiologic prosthetic coverage of the osteotomy surface, the area of 
the cancellous bone surface uncovered by the femoral and tibial components were not evaluated 
intraoperatively.  The area of residual osteotomy might be associated with the volume of blood 
loss and consequently with transfusion rates because osseous hemorrhage is one of the main 
bleeding sources.5 
 
The investigators would like to address limitations in these studies by conducting a prospective, 
randomized trial.  This study will also be collecting outcome measures (Knee Society Score) which 
were noted limitations of these studies.  Additionally, the surgeons will be measuring the amount 
of exposed cancellous bone in the OR. The method to be used is referenced in this protocol. 

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2.3 RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
The surgical techniques used to promote hemostasis will be consistent for all patients, except for 
the use of bone wax applied to the exposed cancellous bone following insertion of the prosthesis.  
There is a potential that patients in the control arm could have increase bleeding. The following 
risks have been shown to be associated with the use of bone wax: failed bone healing, foreign 
body reaction, granuloma growth, thrombosis, infection, and nerve compression 
 
There is a small risk of an unintended breach of confidentiality, as there is in any research study 
that collects subjects’ health information. 
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Bone wax is used on cancellous bone to reduce blood loss during orthopaedic surgery. The 
incorporation of this hemostatic agent in standard TKA procedures could lessen the total blood 
loss intra-operatively and postoperatively for patients randomized to the study group.  
 
Participating in this clinical study will contribute to current medical knowledge of this material. 
The results of this study can make a difference in the care of future patients by providing 
information about the benefits of these interventions. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND 
BENEFITS  
 
Shin and Moo have published on the use of bone wax in total knee arthroplasty, 296 and 50 
patients respectively had bone wax used during their total knee replacement.  Shin, et al found 
that no adverse reactions, including the development of infections or foreign body reactions, 
were observed after the application of bone wax, a finding consistent with those of Moo et al. 5  
Moo found the difference between the bone wax group and the control group with regards to 
transfusion requirements and adverse events following surgery did not reach significance with 
the numbers available; however, trends in favor of the use of bone wax were noted.2 
Drs. Krauss and Segal have been using bone wax on exposed cancellous bone for over 4 years.  
All surgical site infections are reported as part of the Northwell Health System quality metrics.  
Bone wax has been used in 1140 total knee procedures.  For this time period superficial 

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infections were reported in 2 patients and 1 deep infection.  Additionally, the surgeons have 
not had any other issues felt to be related to the bone wax in their patients during their long 
term follow-up visits.      The surgeons technique is to apply the bone wax to the exposed 
cancellous bone after the implant has been cemented in place therefore eliminating the risk for 
any issues with bone ingrowth.  
 
      
3 
OBJECTIVES AND ENDPOINTS 
 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
 
 
 
● Efficacy: 
To assess whether bone 
wax results in superior 
hemostasis in patients 
undergoing primary 
unilateral TKA 
 
 
 
 
 
 
 
 
● Safety: 
To compare the safety 
profile between the 2 
cohorts 
 
 
 
 
 
● To calculate estimated 
perioperative blood loss 
on POD 1 using the      Hb-
balance Formula 
 
 
 
 
 
 
 
 
 
 
● To assess the patients for 
any device adverse events 
related to the use of bone 
wax 
 
 
Use of the      Hb-
balance Formula      
provides a more 
accurate assessment 
of blood loss 
 
 
 
 
 
 
To ensure there are 
no safety issues 
between the two 
cohorts 

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Secondary 
 
 
• To assess whether objective 
and functional outcomes in 
patients undergoing primary 
unilateral TKA differ between 
the two patient cohorts 
 
 
 
 
 
● To determine if there is a 
difference in blood loss 
between the two cohorts  
 
 
● To calculate the Knee Society 
Scores, both objective and 
subjective scores, done 
preoperatively and 8 weeks 
postoperatively  
 
 
 
 
 
● To measure the difference 
between the preoperative and 
POD1 Hemoglobin (Hgb) and 
Hematocrit (Hct) values in the 
two patient cohorts      
The Knee Society 
Score is a validated 
tool to assess both 
objective and 
subjective outcomes.  
The collection of the 
KSS is a standard of 
care for Drs. Krauss 
and Segal’s TKA 
patients.  
 
 
 
These values will be 
used to assess 
hemostasis over time 
 
 
 
 
 
 
  
 
 
 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
• 
A statement of the hypothesis: The use of bone wax on exposed cancellous bone 
surfaces will provide superior hemostasis.  
•  Phase of the trial: NA.  This study is using a FDA approved marketed product as per the 
package instructions.        
• 
A description of the type/design of trial to be conducted: A prospective, randomized, 
single-blinded superiority study to evaluate bone wax use for hemostasis during primary 
unilateral total knee arthroplasty.      
• 
A description of methods to be used to minimize bias: All patients scheduled for 
unilateral total knee arthroplasty will be approached for inclusion in the study. 

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• 
The number of study groups/arms and study intervention duration: This study will 
consist of 2 cohort groups.  One group (50 patients) will have bone wax applied to the 
exposed cancellous surfaces of the bone (treatment group).  The other group (50 
patients) will serve as a control group.  This study is a 1:1 allocation ratio.   The patients 
will not be aware of their randomization assignment.       
• Indicate if single site or multi-site: Single Site-Syosset Hospital Department of 
Orthopaedics 
 
• 
Name of study intervention(s): Bone Wax 
• 
Note if interim analysis is planned and refer to details: No interim analysis is planned. 
• 
Note if the study includes any stratifications: Patient stratification is not needed for the 
randomization.      
• Name of sub-studies, if any, included in this protocol:  Not Applicable  
 
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The investigators would like to address limitations in the studies done by Moo and Shin by 
conducting a prospective, randomized trial.  
 
This study is designed to assess if applying bone wax to exposed cancellous bone during total 
knee arthroplasty provides superior hemostasis.  Patients will be randomized to receive bone 
wax (treatment group) or no bone wax (control group).  Blood loss will be calculated using the      
Hb-balance Formula to provide a      consistent      measurement of perioperative and postoperative 
bleeding.  All other standard of care intraoperative blood minimizing strategies will be consistent 
for these patients.  These strategies include pneumatic tourniquet, intravenous tranexamic acid, 
and spinal anesthesia.  The Inclusion/Exclusion criteria were developed to ensure this 
consistency.   
 
Objective and functional outcomes will be obtained using the 2011 Knee Society Score (KSS).  The 
KSS will be completed preoperatively and postoperatively at the 8 week visit, or the visit closest 
to this time point., (Appendix B- Preoperative/Postoperative 2011 Knee Society Scores) 
Preoperatively patients taking anticoagulants or antiplatelets, with the exception of aspirin 81 
mg daily, will be excluded from the study as these medications could adversely affect 
intraoperative and postoperative bleeding.  Patients with any bleeding dyscrasias will also be 
excluded from the study.  Patients who are unable to stop these products for any reason will be 
excluded from the study.   
Laboratory testing done as standard of care for all preoperative surgical patients are 
comprehensive metabolic panels and complete blood count.  These laboratory values will be 
used to evaluate the inclusion and exclusion criteria for study enrollment. This study does not 
require any study specific laboratory tests.        

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On the operative day patients will be interviewed to confirm their agreement to continue in the 
study. Patients will be re-consented by Dr. Krauss or Dr. Segal if the date of the original consent 
is greater than 30 days from the date of surgery. The inclusion and exclusion criteria will be 
verified prior to study randomization using the laboratory testing done in Pre-surgical Testing 
(PST) and the preoperative medical history documents.  Patients will be randomized to either 
the treatment group (bone wax) or the control arm (no bone wax). The operating room (OR) 
staff will be notified of the treatment arm.  
Intraoperative blood management strategies will be consistent for all subjects to avoid any 
confounding factors which could affect postoperative transfusion requirements. Any patients 
unable to be treated according to the department treatment guidelines will be excluded from 
the study. Intraoperatively blood loss is minimized by anesthetic techniques, pharmacologic 
interventions, and surgical techniques, as per standard of care and department treatment 
guidelines.   
                
The patient and the postoperative hospital staff will be blinded to the treatment arm. The OR 
staff will be trained not to discuss this information with the patient. During the transition of care 
from the OR to the Post Anesthetic Care Unit (PACU) the use of bone wax is not routinely included 
in the verbal patient report.  The lack of this information is not required to effectively manage 
the patient in the postoperative period and will not affect patient care. Postoperatively medical 
care is managed by the hospitalist, medical doctors specializing in the care of hospitalized 
patients.  Hgb and Hct are drawn daily during the patient’s hospitalization as per the standard of 
care. These values will be used to calculate the      Hb-balance Formula.                       
Blood loss will be calculated using the      Hb-balance Formula.       This method is being used to 
provide a more standardized method of calculating blood loss. Eipe and Ponniah showed that 
surgical blood loss was underestimated by 64% when clinical methods are used to assess blood-
soaked sponges and blood lost to suction bottles and the vacuum drain.7         
Following discharge patients will be followed in the outpatient surgical office according to the 
postoperative standard of care visit schedule. Results of      the 2011 KSS Objective and Functional 
Outcome Measurements      administered as part of standard of care at the 8 week postoperative 
visit, or the office visit closest to these time points will be collected for research purposes. 
Patients will be called at 56 days (+2weeks) from the date of surgery for any device related 
adverse events.  This call is standard of care for the department. Three attempts will be made to 
reach the patient before they are considered “lost to follow-up”.   
 
4.3 
JUSTIFICATION FOR DOSE 
      
Not Applicable  
 
4.4 
END OF STUDY DEFINITION 
 

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A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of 
Activities (SoA), Section 1.3.  
 
 
 
 
 
 
5 
STUDY POPULATION 
 
 
5.1 INCLUSION CRITERIA 
 
Inclusion criteria: 
1. Patients scheduled for primary unilateral total knee arthroplasty 
2. Preoperative Hemoglobin >11mg/dL 
3. Preoperative platelet count of >150,000 
4. Age >18  
5. Patient is freely able to provide consent 
6. Patient willing to complete all study related procedures 
 
5.2 EXCLUSION CRITERIA 
1.       Patients unable to take aspirin or apixaban for VTE prophylaxis 
2.       Allergy to any of the ingredients in bone wax (beeswax, paraffin, or isopropyl palmitate)      
3     . Patients taking clopidogrel (Plavix), ticagrelor (Brilinta), or prasugrel (Effient) or any other 
antiplatelet medication (except for aspirin 81 mg) 
     4. Patients unable to get IV TXA for any reason 
     5. Patients requiring anticoagulant treatment prior to surgery 
     6. Any medical condition that in the opinion of the investigator would require special fluid   
management protocols during or after surgery 
     7. Allergy to TXA 

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     8. Blood transfusion within 1 month of surgery 
     9. Patients who are unwilling to undergo blood transfusion, if necessary 
     10. Patients who have habitual opioid use 
     11. Patients who have a psychiatric or mental illness which could impair the consent process 
or ability to complete patient-reported questionnaires 
     12. Fixed motor deficit affecting functional assessment of the knee 
     13. Patients with a contraindication to spinal anesthesia   
     14. Patients receiving erythropoietin therapy for anemia 
     15. Patients who are unable to stop their daily aspirin, aspirin-like products, and/or non-
steroidal anti-inflammatory agents 7 days prior to surgery for any reason 
     16. Patients with a contraindication for the pneumatic tourniquet applied in the operating 
room  
5.3 
LIFESTYLE CONSIDERATIONS 
 
There are no lifestyle modifications or requirements for this study.   
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, and eligibility criteria. 
 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Participation in the clinical trial will be discussed with the patient by Dr. Krauss, Dr. Segal, or a 
designee, when the patient is first scheduled for a unilateral total knee arthroplasty.  The 
investigator will discuss the following:  
● the purpose/objective of the study 
● the study design (e.g., the number of participants) 
● how patients are assigned to the treatment group 

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● participation in this study is not required  
● patients may withdraw from this study at their discretion 
 
Consent will be obtained at any time during the preoperative period.  The patients will be 
provided with contact information for the research staff for any questions or concerns. 
This study will not be including any vulnerable or cognitively impaired patients. 
 
 
 
 
 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
 
Bone Wax is commercially available and is being used in accordance with approved labeling. 
During total joint arthroplasties bone wax is softened and applied firmly on the exposed 
cancellous bone around the prostheses by the orthopaedic surgeon after implant cementing. .        
(Appendix C-Bone Wax Package Insert)  
6.1.2 DOSING AND ADMINISTRATION 
 
Bone wax should be used immediately after removal from the package. Softened Bone Wax is 
applied to the bone edges as indicated by the surgical circumstances and the preference of the 
surgeon.  Exposed cancellous bone surface can vary between patients.  In order to capture this 
variance the surgeons will calculate the amount of exposed bone by the following method: 
 
Once the distal femoral cut and prep for the chamfer cuts and notch cut is complete: 
1.  Measure the distal femur medial to lateral (ML) distance. 
2. Measure the distance from anterior chamfer to most proximal portion of exposed 
anterior femoral bone.  
3. Measure the ML distance of anterior chamfer.  
4. Measure the height of the notch cut, meaning, the anterior posterior (AP) distance 
(notch surface). 

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Those measurements will be collected as well as the femoral implant size.  
 
Calculations of surface area: 
1. ML surface - will be calculated as ML distance - ML width of the implant. That number, 
will be than be multiplied by the combined length of the implant distal condyl and 
anterior chamfer.  
2. Anterior surface - which is mostly a triangle shaped will be calculated as, ML distance of 
anterior chamfer (triangle base) times the triangle height which is distance from 
anterior chamfer edge to most proximal exposed bone on the anterior cut divided by 2. 
From that surface area, the implant anterior flange area will be deducted. 
3. Notch surface - will be calculated as AP notch height X width of the notch. For implant 
size 2-5 there is the same notch width, and 6-10 have same notch width.  
Combining the value of 1+2+3, is the overall exposed bone surface that needs bone wax 
coverage.   
 
 
The exposed bone surface will be document by following grading system:  
 
Grade 1: up to 3 millimeters (mm) of exposed bone 
Grade 2: >3 to 6 mm exposed bone 
Grade 3: >6 mm exposed bone 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Not Applicable  
 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND 
LABELING 
 
Bone wax is a sterile mixture of beeswax, paraffin, and isopropyl palmitate. It is opaque and has 
a waxy odor. Bone wax is available sterile in individual foil envelopes.  
 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
No special storage conditions are required.  
 
 
6.2.4 PREPARATION 

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Using aseptic technique, Bone wax should be warmed to desired consistency by manipulation 
with the fingers. 
 
 
 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
The Biostatistics Unit will develop a randomization procedure using a permuted block design 
within the Biostatistics Randomization Management System (BRMS) system.  Additional details 
of the procedure, including required record keeping, will be further developed upon approval of 
this protocol.  The Biostatistics Unit has extensive experience in implementing and in producing 
detailed documentation for such procedures. The patient will be blinded to their randomization 
group. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
The surgeon and the operating room staff will be notified of the treatment arm prior to the 
start of the surgery.  All patient outcome measurements are part of the standard of care for a 
total knee arthroplasty patient.  
 
6.5 
CONCOMITANT THERAPY 
 
Not Applicable  
 
6.5.1 RESCUE MEDICINE 
 
Not Applicable  
 
 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Not Applicable  
 

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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request.  All 
analyses will be carried out according the ITT principle.  The ITT population will be all patients 
randomized, regardless of whether or not treatment wax administered.  All patients will be 
analyzed in the group to which they were randomized.  
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
 
● Significant study intervention non-compliance  
● A medical condition or situation occurs such that continued participation in the study 
would not be in the best interest of the participant 
The reason for participant discontinuation or withdrawal from the study will be recorded in 
REDCap.  
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for the scheduled 
postoperative visits and is unable to be contacted by the site staff after 3 attempts.  
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
This clinical trial does not require any study specific screening tests or procedures.  Preoperative 
screening done as part of the standard of care for an arthroplasty patient will be used to 
determine patient inclusion and exclusion.  Additionally, there are no required lab testing or 
procedures required for this clinical trial.   
Following discharge patients will be followed in the outpatient office according to the 
postoperative standard of care visit schedule. The 2011 KSS Objective and Functional Outcome 
Measurements will be collected at the 8 week visit, or the office visit closest to these time points. 
Patients will be contacted via phone approximately 56 days      from the date of surgery to capture 
any device related adverse events or other relevant patient outcomes.  These KSS outcomes 
measures and follow-up phone calls are standard of care for the department.  
 
 

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8.2 
SAFETY AND OTHER ASSESSMENTS 
 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward physical or psychological occurrence in a human subject 
participating in research. An AE can be any unfavorable or unintended event including abnormal 
laboratory finding, symptom or disease associated with the research or the use of a medical 
investigational test article. 
Medical Device Reporting: 
This clinical trial is evaluating a commercially available marketed product.  This product is being 
used according to the manufacture’s guidelines.   
This study will adhere to the adverse event reporting regulations of the Centers for Devices and 
Radiological Health (CDRH), part of the Food and Drug Administration (FDA) regulations.  In 
accordance with the Safe Medical Devices Act of 1990 (SMDA) (Public Law 102-629) (21 CFR 
803.32 (c)) ambulatory surgery centers, hospitals, outpatient diagnostic centers and other user 
facilities are required to report all incidents in which a medical device or user error may have 
caused or contributed to the death, serious injury or serious illness of a patient. 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is defined as the period from 
the application of the bone wax to the end of the study treatment follow-up.   
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
Device User Facility Reporting Requirements of Serious Adverse Events: 
A “device user facility” is a hospital, ambulatory surgical facility, nursing home, outpatient 
diagnostic facility, or outpatient treatment facility, which is not a physician’s office. All deaths 
and serious injuries to which the device has or may have caused or contributed will be reported 
to the IRB, FDA and the manufacturer. The user facility will also submit annual reports to the 
FDA by January 1 of each year as described in 21 CFR 803.33. 
Form 3419 Annual User Facility Report 
o Medical Device Reporting Annual User Facility Report - Form FDA3419 

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o Instructions for Completing the Medical Device Reporting Annual User Facility 
Report, Form FDA3419 
8.3.3 Serious Injury or illness definition: 
“Serious injury or illness” means those injuries that are life threatening, result in permanent 
body function impairment or permanent damage to a body structure, or necessitate immediate 
medical or surgical intervention to prevent permanent body function impairment or permanent 
damage to a body structure (21 CFR 803.3) (r).   
A device may have "caused or contributed to" a patient’s death or serious injury, if the death or 
serious injury was or may have been attributed to the device or the device may have been a 
factor in the death or serious injury because of:  
 
o Device failure 
o Malfunction 
o Improper or inadequate device design 
o Manufacture 
o Labeling or 
o User error 
 
 
▪ 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 
SEVERITY OF EVENT 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events. Any non-serious adverse event felt to be related to the study 
device will be captured in the source documents and case report form.   
● Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities.  
• Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening 
or incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
 
8.3.3.2 
RELATIONSHIP TO STUDY INTERVENTION 
 

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All adverse events (AEs) must have their relationship to study intervention (device) assessed by 
the clinician who examines and evaluates the participant based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below. In a clinical trial, the study product must always be suspect.  
 
• Related – The AE is known to occur with the study intervention, there is a reasonable 
possibility that the study intervention caused the AE, or there is a temporal relationship 
between the study intervention and event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
 
 
8.3.3.3 
EXPECTEDNESS  
 
The Principal Investigator will be responsible for determining whether an adverse event (AE) is 
expected or unexpected.  An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the 
study intervention. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last 
visit.  Events will be followed for outcome information until resolution or stabilization. 

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8.3.5 ADVERSE EVENT REPORTING  
 
This clinical trial consists of postoperative total knee arthroplasty patients.  DRE’s common and 
expected in this group of patients include postoperative pain, nausea, hypotension, anemia, and 
dehydration.  Events anticipated and expected in the postoperative arthroplasty patient will not 
be considered an adverse event for collection in the eCRF.  Additionally, there are no study 
interventions for the control group.  This group will be following the standard of care treatment 
for a total knee arthroplasty patient.  Therefore, no adverse events related to the application of 
bone wax will be occurring in this group. 
 
 
 
 
8.3.6 
SERIOUS ADVERSE EVENT REPORTING  
 
The study investigator shall complete an Unanticipated Adverse Device Effect Form and submit 
to the reviewing Institutional Review Board (IRB) as soon as possible, but in no event later than      
5 working days after the investigator first learns of the effect.  The investigator is responsible 
for conducting an evaluation of an unanticipated adverse device effect and shall report the 
results of such evaluation to the Food and Drug Administration (FDA). Thereafter, the 
investigator shall submit such additional reports concerning the effect as FDA requests. 
 
8.3.7 
REPORTING EVENTS TO PARTICIPANTS  
 
Not Applicable 
 
8.3.8 
EVENTS OF SPECIAL INTEREST  
 
Not Applicable 
 
8.3.9 
REPORTING OF PREGNANCY  
 
 Not Applicable 
  
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 

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The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 
 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
This definition could include an unanticipated adverse device effect, any serious adverse effect 
on health or safety or any life-threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relates 
to the rights, safety, or welfare of subjects (21 CFR 812.3(s)).]      
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB). The UP report will include the following information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• A detailed description of the event, incident, experience, or outcome;  
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP;  
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:   
 
• UPs that are serious adverse events (SAEs) will be reported to the IRB within 5 working 
days of the investigator becoming aware of the event.  

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• Any other UP will be reported to the IRB within 5 working days of the investigator 
becoming aware of the problem.  
• All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), 
and the Office for Human Research Protections (OHRP) within 30 days of the IRB 
decision.       
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Not Applicable  
 
 
 
 
 
9 
STATISTICAL CONSIDERATIONS  
                
O 9.1 STATISTICAL HYPOTHESES 
      
 
● Primary Efficacy Endpoint(s):  
 
The primary endpoint is estimated total blood loss measured on POD 1, as calculated by Hb-
Balance      formula.  Blood loss is measured in the morning prior to receiving anticoagulant 
treatment. We hypothesize that applying bone wax during TKA will reduce blood loss on POD 1. 
 
 
 
 
      
● Secondary Efficacy Endpoint(s):      
 
The secondary endpoints are hemoglobin and hematocrit from preoperative to POD 1, as well 
as, the Knee Society Score (KSS), which is collected preoperatively and 8 weeks postoperatively.  
There are two KSS scores; namely, (1)  the patient’s self-assessment of pain, expectations and 
functional outcomes, as well as, (2) the surgeon’s objective measurements.  
 
We hypothesize that applying bone wax during TKA will reduce the quantity of change in 
hemoglobin and hematocrit from preoperative to POD 1. 
 

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We hypothesize that applying bone wax during TKA will positively impact KSS; namely, a 
reduction in pain, an increase in functional outcomes and an increase in alignment, range of 
motion and stability at 8 weeks postoperative. 
 
 
      
 
9.2 SAMPLE SIZE DETERMINATION 
 
Our study will include 50 subjects in each arm (i.e., 100 subjects in total), which is based on 
feasibility and availability of resources.  However, if a formal power calculation were to be 
conducted using a two-sample t-test at a significance level of 0.05, a sample size of 100 subjects 
would be more than sufficient to detect a difference in mean blood loss of about 150 mL to 200 
mL between the control group and the treatment group, which the investigators consider to be 
clinically significant. The table below shows different scenarios for higher and lower mean 
blood loss, as well as, scenarios with a larger standard deviation. The assumed pooled standard 
deviation derived from the study by Moo et al was 271.5 (the standard deviations of the control 
and bone wax groups in the study were 282.7 mL  and 259.8 mL, respectively). 
 
Mean Blood Loss POD 1 
Difference 
(control - bone wax) 
Pooled Std Dev 
Power 
153 
271.5 
80% 
200 
271.5 
95% 
175 
300.0 
82% 
200 
300.0 
91% 
200 
350.0 
81% 
 
 
 
 
 
 
 
9.3 POPULATIONS FOR ANALYSES 
 
All analysis will be conducted on the intention-to-treat (ITT) population.  The ITT population is 
defined as all randomized participants analyzed in the group to which they were randomized, 
regardless of the treatment received.       

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9.4 STATISTICAL ANALYSES 
 
 
9.4.1 GENERAL APPROACH 
 
Descriptive statistics (mean, standard deviation, frequencies and percentages) will be used to 
describe the baseline clinical and demographic characteristics of the sample. The treatment and 
control groups will be compared using formal statistical tests on all other outcomes.           
 
All analyses will be considered significant at p < 0.05 and conducted in SAS v. 9.4 (SAS Institute, 
Inc., Cary, NC).      
 
 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Estimated total blood loss on POD 1 will be compared between the treatment and control 
groups using a two-sample t-test.  If the standard assumptions of Normally distributed residuals 
and equality of variance do not hold, then an appropriate transformation or non-parametric 
method will be used.      
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Separate linear mixed models for repeated measures will be used to compare each secondary 
outcome of interest (hemoglobin, hematocrit and KSS) between the treatment and control 
groups over time from preoperative to postoperative. An appropriate transformation will be 
used for any outcome that does not meet standard assumptions of Normality.           
9.4.4 SAFETY ANALYSES 
 
Adverse events will be reported descriptively as the amount of adverse events are expected to 
be minimal.      
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Not Applicable  
 
9.4.6 PLANNED INTERIM ANALYSES  
 
Not Applicable  
 

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9.4.7 SUB-GROUP ANALYSES 
 
Not Applicable  
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Not Applicable  
 
9.4.9 EXPLORATORY ANALYSES 
 
Not Applicable  
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
  
 
10.1.1 INFORMED CONSENT PROCESS 
 
 
10.1.1.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given 
to the participant and written documentation of informed consent is required prior to starting 
study intervention.   
 
 
10.1.1.2 
CONSENT PROCEDURES AND DOCUMENTATION 
 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved and the participant will be asked to read and review 
the document. The investigator will explain the research study to the participant and answer 
any questions that may arise. A verbal explanation will be provided in terms suited to the 
participant’s comprehension of the purposes, procedures, and potential risks of the study and 
of their rights as research participants.  Participants will have the opportunity to carefully 
review the written consent form and ask questions prior to signing. The participants should 
have the opportunity to discuss the study with their family or surrogates or think about it prior 
to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. Participants must be informed that 
participation is voluntary and that they may withdraw from the study at any time, without 
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records. The informed consent process will be conducted and documented in the source 
document (including the date), and the form signed, before the participant undergoes any 
study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants and the Institutional Review Board (IRB).  Study 
participants will be contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
● Determination of unexpected, significant, or unacceptable risk to participants 
● Demonstration of efficacy that would warrant stopping    
● Insufficient compliance to protocol requirements 
● Data that are not sufficiently complete and/or evaluable 
● Determination that the primary endpoint has been met 
● Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the IRB. 
 
 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators 
and their staff. This confidentiality is extended to cover clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence.     . Research data will be stored in Northwell REDCap 
and the code key will be stored in a research ePHI folder on Northwell server. 
 
 
All research activities will be conducted in as private a setting as possible. 
 
Representatives of the Institutional Review Board (IRB) and regulatory agencies may inspect all 
documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 

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The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB Institutional policies. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Not Applicable  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Provide the name and contact information of the Principal Investigator and the Medical Monitor. 
Principal Investigator 
Eugene Krauss,MD,FAAOS,FACS 
Syosset Hospital, Northwell Health  
221 Jericho Turnpike  
516-496-2637 
ekrauss@northwell.edu 
Steering Committee, Executive Committee, Subcommittee are not applicable for this study. 
 
10.1.6 SAFETY OVERSIGHT 
 
The principal investigator will review safety data in aggregate when overall enrollment reaches 
30 subjects and 60 subjects.      
10.1.7 CLINICAL MONITORING 
 
Not Applicable  
 
 
 
 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The clinical site will perform internal quality management of study conduct, data documentation 
and completion.  An individualized quality management plan will be developed to describe a site’s 
quality management. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
 
10.1.9.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 

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Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets 
for recording data for each participant enrolled in the study.  Data recorded in the electronic case 
report form (eCRF) derived from source documents should be consistent with the data recorded 
on the source documents.  
 
Clinical data, including agent related adverse events (AEs), data will be entered into REDCap 
system. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents. 
 
 
10.1.9.2 
STUDY RECORDS RETENTION  
 
 Study document will be retained for 10 years following study termination. 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) 
requirements. The noncompliance may be either on the part of the participant, the investigator, 
or the study site staff. As a result of deviations, corrective actions are to be developed by the site 
and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their 
policies. The site investigator is responsible for knowing and adhering to the reviewing IRB 
requirements. Further details about the handling of protocol deviations will be included in the 
MOP.  
 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 

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Investigators intend to publish the results of this study. Any published results will only include an 
aggregate of de-identified data. No protected health information will be disclosed outside of 
Northwell Health for the purposes of this research.  
 
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
Eugene Krauss and Ayal Segal, the study doctors, receive financial support from DJO 
Global, the company that is involved in this study. The money this study doctor receives from this 
company is for work as a consultant and is separate from this study.  The study doctors receive 
no payment for any work related to this study. 
 
 
10.2 
ADDITIONAL CONSIDERATIONS-APPENDIX 
 
Appendix A-Total Joint Arthroplasty Pharmacologic Protocols 
 
Appendix B- Preoperative/Postoperative 2011 Knee Society Scores 
 Appendix      C-Bone Wax Package Insert 
      
 
 

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10.3 
ABBREVIATIONS 
The list below includes abbreviations utilized in this template.  However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
AE 
Adverse Event 
ANCO
VA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CM 
Centimeter 
CONS
ORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAA
A 
Food and Drug Administration Amendments 
Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin  
HIPAA 
Health Insurance Portability and 
Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal 
Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
IV 
Intravenous 
KSS 
Knee Society Score 
LOS 
Length of stay 
LSME
ANS 
Least-squares Means 

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MedDR
A 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
POD 
Postoperative Day 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOA 
Schedule of Activities 
TKA 
Total Knee Arthroplasty  
TXA 
Tranexamic Acid  
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.4 
PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11 REFERENCES  
 
 
      
1. Dunne JR, et al. Perioperative anemia: an independent risk factor for infection, 
               Mortality, and resource utilization in surgery. J Surg Res 2002; 102(2):237 
 
 
2. Moo, I. H., Chen, J. Y., Pagkaliwaga, E. H., Tan, S. W., & Poon, K. B. (2017). Bone Wax Is 
Effective in Reducing Blood Loss After Total Knee Arthroplasty. The Journal of 
Arthroplasty, 32(5), 1483–1487. doi: 10.1016/j.arth.2016.12.028reduces blood loss and 
transfusion rates in total hip and total knee arthroplasty.  J of arthroplasty 
2013;28:1473-1476 
3. Porter SB, White LJ, Osagiede O, et al. Tranexamic acid administration is not associated 
with an increase in complications in high-risk patients undergoing primary total knee or 
total hip arthroplasty: a retrospective case-control study of 38,220 patients. J 
Arthroplasty. 2020;35:45–51.e3. https://doi.org/10.1016/j.arth.2019.08.015. 
 
4. Rodgers A, Walker N, et al. Reduction of postoperative mortality and morbidity with 
epidural or spinal anesthesia: results from overview of randomised trials. BMJ 2000;321      
 
5. Shin KH, Choe JH, Jang KM, Han SB. Use of bone wax reduces blood loss and transfusion 
rates 
after 
total 
knee 
arthroplasty. 
Knee. 
2020 
Oct;27(5):1411-1417. 
doi: 
10.1016/j.knee.2020.07.074. Epub 2020 Aug 19. PMID: 33010755. 
 
6. Gibon E, Courpied, J-P. Total joint replacement and blood loss: what is the best equation? 
Inter Ortho. 2013; 37:735-7397. Eipe NP, Ponniah M. Perioperative blood loss 
assessment-how accurate? Indian J Anaesth. 2006; 50(1):35-38 
 
7. Eipe NP, Ponniah M. Perioperative blood loss assessment-how accurate? Indian J.      
Anaesth. 2006; 50(1):35-38 
 
 
Appendix: 
 
A. Total Joint Arthroplasty Pharmacologic Protocols  
B. Preoperative/Postoperative 2011 Knee Society Scores  
C.                Bone Wax Package Insert 

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