Clinical trial NCT02227446
Conditions: Post Operative Surgical Site Infection
Keywords: Surgical site infection risk prevention Bacterial species type and antibacterial sensitives
Sponsor: Major Extremity Trauma Research Consortium
Start date: 2014-10-01; Completion date: 2019-11-01
Enrollment: 1036 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The Vancomycin Study is a multi-center, prospective randomized controlled trial that will compare the proportion of deep surgical site infections within 6 months in patients treated with local Vancomycin powder compared to those treated without local Vancomycin powder at the time of fracture fixation.

Detailed description:
Primary Aim: Compare the proportion of deep surgical site infections within 6 months in patients treated with local Vancomycin powder compared to those treated without local Vancomycin powder.

Primary Hypothesis: The proportion of deep surgical site infections will be lower for patients treated with local Vancomycin powder.

Secondary Aim #1: Compare antibiotic sensitivities of the bacteria in the patients who develop deep surgical site infections in study patients treated with local Vancomycin powder compared to those treated without local Vancomycin powder.

Hypothesis 1: In the patients who develop infections, the antibiotic sensitivity profiles between patients treated with local Vancomycin powder will be non-inferior to those treated without local Vancomycin powder.

Secondary Aim #2: Build and validate a risk prediction model for the development of deep surgical site infections in patients treated without local Vancomycin powder. (b) Explore whether the effect of local Vancomycin powder is modified by the predicted risk of infection.

Hypothesis 2: Patient (e.g. medical co-morbidities) and injury (e.g open fractures) factors will be highly predictive of infection risk.

Hypothesis 3: Patients with higher predictive risk will experience greater benefit from local antibiotics.

Arms: arm 1: Participants in the treatment group will receive the study intervention of a maximum dose of 1000mg of Vancomycin antibiotic powder in their wound bed, which is placed right before wound closure. Vancomycin antibiotic powder may be combined with normal saline as per clinical practice at the participating institution.

In addition, participants in this group will receive standard of care treatment for their injury, to include all institution specific standard treatment (prophylactic and otherwise) for preventing and treating infection. arm 2: Participants in this group will receive standard of care treatment for their injury, to include all institution specific standard treatment (prophylactic and otherwise) for preventing and treating infection. Participants in this group will not receive local Vancomycin antibiotic powder.
Interventions: intervention 1: Vancomycin antibiotic powder
Intervention descriptions: intervention 1: At the time of fracture fixation 1000 mg of Vancomycin powder placed into the wound during wound closure.

Protocol documents:
Prot_ICF_000.pdf: 
 
METRC VANCO Protocol v 2  10/6/2014 
i 
Major Extremity Trauma Research Consortium (METRC): 
Local Antibiotic Therapy to Reduce Infection after Operative Treatment of Fractures at High 
Risk of Infection: A Multicenter Randomized, Controlled Trial  
[FDA IND #119891] 
NCT02227446 
 
Sponsored by: DOD CDMRP  
 
Contract Number:  W81XWH-10-2-0134  
 
Principal Investigator/Protocol Chair: Robert V. O’Toole, MD 
 
Medical Monitor: Marc Swiontkowski, MD 
 
Version 2.0 
 
10/6/2014 
 
This template is adapted from the ICH guidance document E6 (Good Clinical Practices), 
Section 6. 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff, and applicable independent ethics 
committees or institutional review boards.  The contents of this document shall not be 
disclosed to others without written authorization from METRC (or others, as applicable), 
unless it is necessary to obtain informed consent from potential study participants. 


 
METRC VANCO Protocol v 2  10/6/2014 
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Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff, and applicable independent ethics 
committees or institutional review boards.  The contents of this document shall not be 
disclosed to others without written authorization from METRC (or others, as applicable), 
unless it is necessary to obtain informed consent from potential study participants. 


 
METRC VANCO Protocol v 2  10/6/2014 
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Signature Page  
 
The signature below constitutes the approval of this protocol and the attached appendices, and 
provides the necessary assurances that this trial will be conducted according to all stipulations of 
the protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
The Lead Principal Investigator (Protocol Chair) should sign Signature Page 1.  A copy of this 
Signature Page 1 should be filed with the holder of the Regulatory documents and a copy should 
be maintained at the site. 
 
Principal Investigator:  _______________________________________________ 
                                                                    Print/Type 
 
Signed: 
 
Date: 
 
 
Name/Title 
 
 
 


 
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Table of Contents 
Signature 
Page..................................................................................................................... 
iii 
List of General 
Abbreviations/Terminology…………………………………………… 
List of METRC 
Abbreviations/Terminology…………………………………………… 
Protocol Summary…………………………………………………………………….. 
7 
8 
9 
1. KEY ROLES………………………………………………………………………...... 14 
2. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE………...... 15 
2.1 Background 
Information…………………………………………………………….. 
15 
2.2 
Rationale……………………………………………………………………………… 
16 
2.3 Potential Risks and 
Benefits………………………………………………………… 
 
     2.3.1 Potential 
Risks……………………………………………………………………………. 
 
     2.3.2 Potential 
Benefits………………………………………………………………………… 
 
3. STUDY OBJECTIVES………………………………………………………………. 16 
3.1 Primary 
Objective…………………………………………………………………… 
16 
3.2 Secondary 
Objectives………………………………………………………………… 
16 
3.3 Exploratory 
Objectives………………………………………………………………. 
16 
4.  STUDY 
OVERVIEW………………………………………………………………… 
17 
5. STUDY POPULATION……………………………………………………………… 17 
5.1 Description of the Study 
Population………………………………………………… 
17 
     5.1.1 Participant Inclusion Criteria………………………………………………………… 
18 
     5.1.2 Participant Exclusion 
criteria………………………………………………………….. 
18 
     5.1.3 Co-Enrollment 
Guidelines………………………………………………………………. 
19 
5.2 Strategies for 
Recruitment…………………………………………………………… 
19 
6. STUDY PROCEDURES…………………………………………………………… 
19 


 
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6.1 Screening and Enrollment 
19 
     6.1.1 Screening 
19 
     6.1.2 Consent and Enrollment 
19 
     6.1.3 Assessing Capacity to Consent and Consenting a Proxy Respondent 
20 
     6.1.4 Informed Consent Process or Assent for a minor 
21 
6.2 Baseline Data Collection 
22 
     6.2.1 Medical Record Review 
22 
     6.2.2 Clinical Assessment 
22 
     6.2.3 Participant Interview 
23 
6.3 Participant Follow up and Data Collection 
23 
     6.3.1 Follow-up Visit Schedule 
23 
     6.3.2 Clinical Assessments 
23 
     6.3.3 Participant Interviews 
23 
     6.3.4 Retention 
23 
     6.3.5 Final Study Visit 
24 
     6.3.6 Early Termination Visit 
24 
6.4 Study Endpoints 
24 
     6.4.1 Primary Endpoint 
24 
     6.4.2 Secondary Endpoint 
25 
     6.4.3 Exploratory Endpoint 
26 
     6.4.4 Substudy Endpoint 
26 
7. STUDY TREATMENTS 
27 
7.1 Study Treatment #1 
27 
     7.1.1 Description of Treatment 
27 
     7.1.2 Potential Risks and/or adverse effects 
27 
7.2 Study Treatment #2  
28 
     7.2.1 Description of Treatment 
28 
     7.2.2 Potential Risks and/or adverse events 
28 
8. ASSESSMENT OF SAFETY……………………………………………………… 
28 
8.1 Definitions…………………………………………………………………………. 
29 
     8.1.1 Adverse event………………………………………………………………………….. 
29 
     8.1.2 Unanticipated problem………………………………………………………………. 
29 
     8.1.3 Serious Adverse Event……………………………………………………………….. 
29 
8.2 Methods and Timing for Assessing, Recording, and Analyzing, Managing 
Safety Parameters…………………………………………………………………….. 
29 
     8.2.1 Methods and Timing of Assessment…………………………………………………. 
29 
     8.2.2 AE/SAE Grading and Relationship Assignment…………………………………… 
30 
     8.2.3 Recoding and Documentation……………………………………………………….. 
30 
     8.2.4. Management of Adverse Events…………………………………………………….. 
30 
8.3 Adverse Event Reporting Procedures…………………………………………… 
31 


 
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     8.3.1 Local Reporting Requirements………………………………………………………. 
31 
     8.3.2 SAE and Unanticipated Problem Reporting Requirements……………………… 
31 
     8.3.3 METRC Coordinating Center Reporting Responsibilities………………………. 
31 
     8.3.4 Department of Defense Reporting Requirements…………………………………. 
31 
8.4 Reporting Pregnancy……………………………………………………………… 
33 
8.5 Type and Duration of the Follow-up of Participants After Adverse Events….. 
33 
8.6 Modifications of Study Agent(s)/Intervention(s) for a Participant…………….. 
33 
8.7 Halting Rules for the Protocol……………………………………………………. 
33 
8.8 Stopping Rules for an Individual Participant/Cohort………………………….. 
33 
8.9 Premature Withdrawal of a Participant………………………………………… 
33 
8.10 Replacement of a Participant Who Discontinues Study Treatment………….. 
33 
9. MONITORING …………………………………… 
34 
9.1 Site Monitoring Plan…………………………………………………………….. 
34 
9.2 Safety Monitoring Plan………………………………………………………….. 
34 
     9.2.1 Safety Review Plan by the DSMB………………………………………………… 
34 
10. STATISTICAL CONSIDERATIONS………………………………………….. 
35 
10.1 Overview and Study Objectives…………………………………………………. 
35 
10.2 Sample Size Considerations…………………………………………………….. 
35 
10.3 Randomization…………………………………………………………………… 
36 
10.4 Missing Data and Measures to Minimize Bias…………………………………. 
37 
10.5 Planned Interim 
Analysis…………………………………………………………… 
38 
10.6 Analysis Plan……………………………………………………………………… 
38 
11. QUALITY CONTROL AND QUALITY ASSURANCE………………………. 
39 
11.1 Data Quality Assurance…………………………………………………………. 
39 
11.2 Training and Certification of Centers………………………………………….. 
39 
12. ETHICS/PROTECTION OF HUMAN SUBJECTS……………………………. 
39 
12.1 IRB/Ethics Committee…………………………………………………………… 
39 
12.2 Exclusion of Women, Minorities, and Children (Special Populations)………. 
39 
12.3 Participant Confidentiality………………………………………………………. 
39 
12.4 Study Discontinuation……………………………………………………………. 
40 
13. DATA HANDLING AND RECORD KEEPING………………………………... 
40 
13.1 Data Management Responsibilities……………………………………………... 
40 
13.2 Data Capture Methods………………………………………………………….. 
41 
13.3 Types of Data…………………………………………………………………….. 
41 
13.4 Source Documents and Access to Source Data/Documents…………………… 
41 
13.5 Study Records Retention………………………………………………………… 
41 
13.6 Protocol Deviations………………………………………………………………. 
42 
14. PUBLICATIONS POLICY……………………………………………………… 
42 
15. SCIENTIFIC REFERENCES…………………………………………………… 
42 


 
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16. APPENDICES 
49 
     Appendix A: Study Contacts 
Roster…………………………………………………… 
49 
     Appendix B: Protocol 
Committee……………………………………………………… 
50 
     Appendix C: Data Collection 
Schedule………………………………………………… 
51 
     Appendix D: Consent 
Template………………………………………………………... 
53 
     Appendix E: Evaluation to Give 
Consent………………………………………………. 
59 
     Appendix F: Study Brochure 
Insert……………………………………………………. 
60 
     Appendix G: Interviews 
62 
 
 
 


 
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List of General Abbreviations/Terminology 
 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CIB 
Clinical Investigator’s Brochure 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee 
FDA 
Food and Drug Administration 
FWA 
Federal-Wide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
Investigational Device Exemption 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MedDRA © 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NDA 
New Drug Application 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
WHO 
World Health Organization 
 


 
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List of METRC Abbreviations/Terminology 
 
AFIRM  
The Armed Forces institute of Regenerative Medicine 
CDMRP                          
Congressionally Directed Medical Research Program.   
CCCS  
 
 
 
Civilian Core Clinical Sites   
 
DOD  
 
 
 
Department of Defense 
DOD HRPO 
DOD Human Research Subject Protection Office.   
DOD PRORP  
Department of Defense Peer Reviewed Orthopaedic 
Research Program  
Master Consent Form 
Template consent form designed for study by the MCC  
Master IRB application 
Template IRB application designed for study by the MCC  
MCC  
 
 
 
METRC Coordinating Center of the Consortium  
MCC Study Manager 
Principal site contact for Research Coordinators at sites 
MTF Core Clinical Sites 
Military Treatment Facilities Core Clinical  
OETRP 
 
 
 
Orthopaedic Extremity Trauma Research Program 
PPM  
 
 
 
Policy and Procedure Memorandum 
SCC 
 
 
 
 
Satellite Clinical Sites  
AI 
 
 
 
 
Site Associate Investigators. 
RC 
 
 
 
 
Site Research Coordinator 
RS 
 
 
 
 
Site Research Staff  
Study Number  
 
 
Protocol identification number 
Study Principal Investigator  
Lead Investigator on a protocol 
Study Protocol Committee 
Protocol development  
REDCap 
Research Electronic Data Capture System  
USAMRMC                                        United States Army Medical Research and Material 
Command 
 
 


 
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PROTOCOL SUMMARY  
 
Title: Local Antibiotic Therapy to Reduce Infection after Operative Treatment of Fractures at 
High Risk of Infection: A Multicenter Randomized, Controlled Trial  
Sponsor: DOD PRORP 
Type of study: Prospective Randomized Controlled Trial 
 
Primary Aim:  Compare the proportion of deep surgical site infections within 6 months in 
patients treated with local Vancomycin powder compared to those treated without local 
Vancomycin powder. 
 
Primary Hypothesis: The proportion of deep surgical site infections will be lower for patients 
treated with local Vancomycin powder. 
 
Secondary Aim #1:  Compare antibiotic sensitivities of the bacteria in the patients who develop 
deep surgical site infections in study patients treated with local Vancomycin powder compared to 
those treated without local Vancomycin powder. 
 
Hypothesis 1: In the patients who develop infections, the antibiotic sensitivity profiles between 
patients treated with local Vancomycin powder will be non-inferior to those treated without local 
Vancomycin powder. 
 
Secondary Aim #2:  Build and validate a risk prediction model for the development of deep 
surgical site infections in patients treated without local Vancomycin powder. (b) Explore 
whether the effect of local Vancomycin powder is modified by the predicted risk of infection. 
 
Hypothesis 2: Patient (e.g. medical co-morbidities) and injury (e.g open fractures) factors will be 
highly predictive of infection risk. 
 
Hypothesis 3:  Patients with higher predictive risk will experience greater benefit from local 
antibiotics. 
 
Study design: The proposed study is a multi-center, prospective randomized controlled trial 
comparing treatment with and without the local Vancomycin powder at the time of fracture 
fixation.   
 
Study duration: 24 months; 12 month enrollment period, 6 month patient follow up.  
 


 
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Sample size: 500 patients will be consented per arm.  
 
Number of study sites: Over 15 sites will be included which is made up of a Combination of 
subset of 24 Core METRC and 4 MTFs not able to enroll in competing METRC studies, and 30+ 
METRC satellite sites.  
 
Inclusion criteria  
1.   All “high energy” tibial plateau fractures treated operatively with plate and screw fixation. 
We define “high energy” tibial plateau fractures as patients who are either: 
1.1 Initially treated with an external fixation (with or without limited internal fixation) 
and treated definitively more than 3 days later after swelling has resolved. 
1.2 Any open type I, II, or IIIA fracture, regardless of timing of definitive treatment. 
1.3 Any tibial plateau fracture associated with ipsilateral leg compartment syndrome 
fasciotomy wounds. 
 
2.   All “high energy” pilon (distal tibial plafond) fractures treated operatively with plate and 
screw fixation. We define “high energy” pilon fractures as patients who are either: 
2.1 Initially treated with an external fixation (with or without fibula fixation or 
limited internal fixation) and treated definitively more than 3 days later after 
swelling has resolved. 
2.2 Any open type I, II, or IIIA fracture, regardless of timing of definitive treatment. 
2.3 Any tibial pilon fracture associated with ipsilateral leg compartment syndrome 
fasciotomy wounds. 
 
3.   Ages 18 to 80 years 
4.   Patients may have co-existing non-tibial infection, with or without antibiotic treatment. 
5.   Patients may have risk factors for infection including diabetes, immunosuppression 
from steroids or other medications, HIV, or other infections. 
6.   Patients may have a head injury 
7.   Patients may have a portion of the fixation (e.g. fibula fixation in pilon or percutaneous 
screws across a tibial plateau fracture) prior to definitive plate fixation, at the initial 
surgery before randomization. 
8. Patients may have other orthopedic and non-orthopaedic injuries. 
9. Patients may have pre-existing musculoskeletal injuries, be non ambulators, or have spinal 
cord injuries. 
10. Women and minorities are included.  
 
Exclusion criteria  
1.  The study injury: tibial plateau, pilon, is already infected at time of study enrollment. 
2.   Patient speaks neither English nor Spanish. 
3.   Patients who have already had definitive fixation prior to enrollment in the study. 


 
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4.   Severe problems with maintaining follow-up (e.g. patients who are homeless at the time of 
injury or those how are intellectually challenged without adequate family support). 
5.   Patients with allergies, drug administration reactions, or other sensitivities to Vancomycin 
(such as a history of Redman’s Syndrome). 
6.   Pregnancy. 
7.   The study injury is a type IIIB or IIIC open fracture. 
 
Outcome measures  
 
Primary Outcome Measure: Surgical Site Infection.  The main outcome measure will be 
the presence of clinically significant deep SSI in the first 24 weeks after surgery, as 
determined by CDC guidelines for determining surgical site infection 24,34,51. These guidelines 
were developed to provide clear, objective criteria for evaluating surgical wounds and 
determining the presence or absence of infection. The CDC criteria is currently 3 months for 
surgical site infection and our pilot data indicate that 85% of the infections in this population 
happened in the first 3 months 72.  To help capture more infections, we have moved the 
timeframe back to 6 months. 
 
Wound characteristics will also be evaluated using the ASEPSIS score 15,16,84,85. In this system 
wounds are scored using the weighted sum of points assigned for predetermined criteria 
including the need for Additional treatment, presence of Serous drainage, Erythema, Purulent 
exudates, Separation of deep tissues, the Isolation of bacteria, and the duration of patients Stay 
(ASEPSIS).  This system of wound scoring complements the CDC guidelines by providing a 
means to grade the severity of infection as does the METRC standardized infection CRF 
which records culture data, laboratory values (as obtained as part of standard clinical care by 
site), and other parameters to help insure validity of the primary outcome measure.   
 
In keeping with the CDC definition, we will define deep infections as those that require 
operative treatment, and superficial infections as those that are treated without operative 
intervention.  Based on our previous oxygen study using the same patient population, we expect 
that 85% of infections in this patient population to require operative treatment and to have an 
overall deep infection rate around 11.5% 72. 
 
Secondary Outcome Measure: Bacterial Sensitivities: Secondary outcome measures in 
this study include culture data in the group that becomes infected. All deep surgical site 
infections will have sterile intraoperative wound cultures taken, as is currently performed in 
routine clinical practice. Sensitivities of the isolated bacteria, which are also determined 
routinely in current clinical practice, will be recorded for analysis.  Theoretically, the use of 
the local Vancomycin powder might influence the sensitivity of bacteria to certain antibiotics 
in the patients who become infected.   
 


 
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It might be anticipated that bacteria in patients with infections that develop in the treatment 
group might be less susceptible to Vancomycin as this is the antibiotic used in this technique.    
The most common bacterial isolates in infection after orthopaedic fracture care are methicillin 
resistant staph. aureus and methicillin resistant coagulase negative Staphylococci.  These 
bacteria are frequently susceptible to Vancomycin, and the occurrence of Vancomycin 
resistant (meaning the drug is not effective against the bacteria) strains of staph aureus and 
coagulase negative staphylococci would be clinically concerning.  We do not anticipate this 
occurring but will use the rate of Vancomycin sensitivity as an outcome measure in the 
patients with staph. infections as a secondary outcome measure.  The appearance of additional 
clinically relevant bacterial susceptibilities will also be monitored as part of the study. 
 
Risk Factors for Infection: All demographic characteristics of the patient, the descriptors of 
the injury, and details of the surgical treatment that would be available prior to the implant of 
the local Vancomycin powder will be collected for analysis regarding determination of a model 
to predict infection risk in this patient population.  This analysis will aid clinicians in 
determining risk for postoperative infection as well as help determine which patients are most 
likely to benefit from the local Vancomycin powder technique. 
 
Demographic variables will include age, presence of co-morbidities such as 
diabetes, smoking history, history of prior musculoskeletal infection, and history of 
infection within the past 30 days. 
 
Injury descriptors will include injury mechanism, open or closed fracture type, AO 
classification of the fracture type, other orthopaedic injuries, and other non-
orthopaedic injuries. 
 
Treatment parameters will include time from injury to definitive treatment, time 
from injury to external fixation (for the tibial plateau and pilon fractures), and 
surgical approaches used (for the tibial plateau and pilon fracture). 
 
 
 
 
 
 
 
 
 
 
 
 
1. KEY ROLES  


 
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Protocol Committee- Responsible for developing a detailed study protocol, provides oversight on 
study progress and acts to correct deficiencies in the conduct of the study. This committee also 
drafts the main publications related to the study. 
Steering Committee- Steering Committee is the decision making body of the Consortium and 
makes decisions regarding study design issues, study procedures, allocation of study resources 
and priorities for meeting competing demands of the Consortium and individual studies. The 
Steering Committee is composed of Site Investigators from each core METRC clinical center, 
the Department of Defense Program Officer for METRC, the orthopaedic consultants from the 
Army, Navy and Air Force, regional representatives of Satellite Clinical Centers, and the 
Director, Deputy Director, Principal Biostatistician and Principal Economist of the Coordinating 
Center. The Steering Committee is responsible for approving the protocol.   
METRC Coordinating Center- Responsible for maintaining all study documentation, developing 
and maintaining the master IRB application and consent, circulating any changes to study 
documents including protocols, case report forms, and IRB materials to each participating center, 
providing daily oversight and management of study implementation, providing payment to sites 
for patients enrolled, performing site monitoring, data quality control and analysis of study 
results.   
Core and Satellite Clinical Sites- Responsible for the conduct of clinical studies including patient 
enrollment, performing study procedures, data collection and conducting study follow-up visits.  
Publication Committee- Responsible for reviewing manuscripts prior to journal submission and 
reviewing presentations prior to presentation; for mediating and settling disputes and conflicts 
among study investigators over publication or presentation priorities, authorship, and any other 
issues related to publications or presentations; for preparing and maintaining a list of concepts 
for publications and preparing and maintaining a list of approved METRC publications, which 
shows the status of each manuscript from initiation through publication. 
DSMB- Independent Data and Safety Monitoring Board (DSMB) appointed by DOD, 
responsible for monitoring the accumulated interim data as the trial progresses to ensure patient 
safety and to review efficacy, evaluate recruitment, and assess overall data quality.  
Medical Monitor- Responsible for providing medical guidance and overseeing patient safety for 
the study. The MM participates in determining the course of action necessary to meet safety 
goals and objectives. This is achieved through the review of safety reports; resolving safety 
issues; and interacting with Principal Investigators.  


 
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2. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
2.1 Background Information 
The treatment of high-energy military fractures continues to have poor outcomes and is 
associated with high rates of infection.  The use of local antibiotics associated with fracture 
hardware has potential to reduce complications by lowering infection rates in these patients. 
 
Our hypothesis is that the use of sterile local Vancomycin powder for fractures at high risk for 
infection will reduce infection rates and therefore improve outcomes compared to treatment 
without the local antibiotics.  The results of this trial have potential to reduce surgical site 
infection within both the military and civilian sectors and therefore improve patient outcomes 
from these potentially devastating injuries. 
 
1.2 Problem Definition: Infection after Fracture Fixation 
Infection continues to be a common complication associated with treatment of high-energy 
military fractures 20,22,33,38,43,59,62. As with high-energy civilian fractures, a high rate of hospital 
re-admission for complication have been observed, and these complications have been linked to 
poor medium and long-term outcomes11,31.  Hospital re-admission for complications such as 
infection was one of the most important predictors of poor outcome in the Lower Extremity 
Assessment Project (LEAP) study, a prospective multi-center study on high- energy trauma 11.   
The LEAP study reported that the re-hospitalization rate for complications after severe open 
fractures is as high as 57% and one of the major drivers of hospital re- admission is deep 
infection 11,31. 
 
Traditional treatment protocols for high energy lower extremity fractures have demonstrated 
rates of surgical site infection and osteomyelitis ranging from 14.3%% - 60.0% 
11,20,22,31,33,38,43,59,62,74 in both military and high energy civilian settings.  Traditional treatment 
protocols typically utilize metallic hardware (plates and screws or nails) for fracture fixation, 
which have the disadvantage of placing metal within the fracture site. Multiple studies 
demonstrate that infection rates tend to increase whenever hardware is placed within a wound 
67,68,71, likely due to the difficulty the immune system has in clearing bacteria from the biofilm 
that develops on metallic surfaces 28,67. High- energy military injuries have a particularly high 
risk of infection 20,22,33,38,43,59,62. 
 
Surgical site infection is a major treatment challenge in the military, but it continues to cause 
significant morbidity in civilian applications as well.  Surgical site infection in general is the 
most common potentially preventable post-operative complication with estimates of $1.8 billion 
spent in treatment of surgical site infection each year in the United States 13,14,71. Any treatment 
strategy that could reduce surgical site infection would certainly make an important contribution 
to the care of our wounded soldiers, but also the care of orthopaedic trauma patients in general. 
 
Intravenous (IV) antibiotics are routinely given at the time of all fracture fixation surgery to 
decrease the rate of surgical site infection 13,14, 63,90.  The efficacy of prophylactic IV antibiotics 


 
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and the importance the timing of the delivery of these antibiotics have been well studied and 
shown to be efficacious 13,14, 63, 90.  The use of these systemic antibiotics is currently the standard 
of care. 
 
Despite the success in using IV antibiotics as a prophylaxis against wound infection, in some 
ways systemic antibiotics are an inefficient strategy to prevent infection associated with the 
surgical treatment of fractures. The mechanism of the beneficial effect of systemic antibiotics is 
thought to be in delivery of antibiotics to the site of the surgery; however antibiotics are 
delivered throughout the body where it is not needed.  This limits the amount (dose) of 
antibiotics that can be delivered at the surgical site else risk toxicity to other remote organ 
systems. 
 
Intravenous antibiotics also are only delivered to tissues that have a blood supply since the 
antibiotics are administered into the systemic circulation.  Tissues that are traumatized frequently 
have a compromised blood supply.  Further, all foreign material such as the metallic plates used 
in fracture fixation, have no blood supply so antibiotics are not delivered to the plate surface 
where bacteria commonly adhere and colonize the surgical site. 
 
Local antibiotics hold promise to reduce surgical site infection in general 91,92,96 and in particular 
in high energy fracture patients such as those seen in military injuries.  The mechanism of 
infection after fracture surgery is typically that bacteria adhere to the metal plates at the time of 
surgery and “colonize” the plate 28,67,68. The bacteria create a “biofilm”, a protective layer that 
sequesters the bacteria from the body’s immune system and allows the bacteria to multiply and 
eventually lead to surgical site infection 28,67,68.  Local antibiotics attempt to disrupt this cycle by 
sterilizing the wound bed and preventing the development of the biofilm 30,36,44,71. 
 
Traditionally orthopaedic trauma surgeons who wish to use this concept of local antibiotics are 
forced to create their own antibiotic delivery devices. Surgeons create “antibiotic beads” out of 
cement (polymethy methacralate) that is impregnated with antibiotics and then placed within the 
wound 93,94,95.  Fracture surgeons also use this concept when they create an intramedulary nail 
out of antibiotic impregnated cement to help clear infections after fracture treatment 6. 
 
Antibiotic beads are an imperfect solution as they require removal of the antibiotic beads at 
another surgery, and the beads themselves take up space making them impractical in many 
fracture types as they may make wound closure difficult or impossible.  There are some 
dissolvable compounds that can be placed in a wound, but the existing products tend to drain 
fluid that looks like drainage associated with infection so they are rarely used in clinical practice 
for prophylaxis against infection. 
 
Although there is great interest in the use of local antibiotics to help decrease the rate of 
infection, currently orthopaedic trauma surgeons rarely have a way to implement this strategy. 
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associated with high rates of infection and significant local tissue damage making intravenous 
antibiotics less efficacious.  A strategy for sterilizing the wound at the time of fracture surgery 
and preventing the colonization of the orthopaedic implants may have significant clinical benefit, 
but to date no such technique is widely used for these patients. 
 
1.4   Novel Approach: Local Vancomycin Powder 
 
Implantable medical devices incorporating antibiotics to reduce the risk of implant related 
infection have been used clinically in orthopedic surgery for decades 36 and continue to evolve 68.  
The concept of a sleeve or pouch added to an implantable device to reduce infection has been 
successfully demonstrated with cardiac pacemakers 30. These FDA-approved products have been 
demonstrated clinically to be safe and effective outside the realm of orthopaedics but have not 
yet reached the stage of clinical use in orthopaedics. 
 
In contrast, recently several clinical studies in the spine literature have emerged describing the 
use of local Vancomycin powder to reduce surgical site infection 97,98,99,100,102.  These studies 
demonstrated that deep infections were four times as likely in patients who did not receive the 
local Vancomycin powder prophylaxis 97,98,99,100,101 and demonstrated a reduction in the cost of 
care.  These studies are retrospective in nature and suffer from limitations such as selection bias, 
but the initial data have demonstrated remarkable reduction in infection rates in the group using 
the local Vancomycin powder.  Additionally, these studies have demonstrated no known 
complications or side effects of the local use of Vancomycin 97,98,99,100. In one study 80% of these 
patients had no systemic Vancomycin levels detected and 20% had very low levels that were 
well below clinical importance indicating the likely lack of effect of the technique on distant 
organs 98. 
 
The surgical technique employed using local Vancomycin powder has been to place the sterile 
powder directly in the wound over the hardware and tissues at the time of wound closure 
97,98,99,100.  It is thought that this creates the “kill zone” for bacteria that inhibits biofilm 
formation.  As there is essentially no carrier for the antibiotics, the antibiotics are likely gone 
within a day or even less time.    
 
It is unknown how long the antibiotics must be present in the wound to be effective, but the spine 
data clearly indicates that this method of delivery appears to be efficacious. It appears that there 
may be a critical window right around the time of surgery to reduce the rate of surgical site 
infection and local Vancomycin powder may play a crucial role in this period.   Other methods 
that reduce surgical site infection such as IV antibiotics 90 are very time dependent and must be 
given very near the time of the surgical incision for efficacy.   Further, from a concern for 
development of resistant bacteria it is preferable to have a high dose with broad killing over a 
short time period as would be present with this technique, than to have lower doses present over 
longer time periods which might be the case with antibiotics in longer acting carriers. 
 


 
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Although there is strong scientific rationale and reasonable evidence from the spine literature 
indicating safety and hinting at efficacy, there is no literature investigating this technique in 
extremity fracture surgery at risk for infection, which is of significant interest to both the military 
and civilian trauma populations.  Anecdotally, some leading orthopaedic trauma surgeons 
nationally have used the technique for high-risk patients without complication and some centers 
(Vanderbilt for example) have used the technique for years for this application.  Having said that, 
there is no literature to date supporting its use in patients at high risk of infection. 
 
Vancomycin powder is appealing in technique as it is potentially applicable to every patient 
treated with fractures at high risk for infection in both the military and civilian domains.  
Additionally, there is nothing to theoretically limit such a concept from being used with any type 
of hardware, thus increasing the potential impact of the product on clinical practice.  Surgeons 
could choose to use the technique in patients of high risk of infection. 
 
There are several potential advantages of local Vancomycin powder over antibiotic coated 
implants.  The first is ease of study design.  Since Vancomycin is already clinically used, it was 
straightforward to obtain FDA approval for the study. Additionally, Vancomycin powder is low 
cost (<$10/dose) compared with the likely expense associated with these newer emerging 
technologies.  Further, surgeons, hospitals, and operating room personnel are already familiar 
with Vancomycin powder so there are almost no surgeon barriers to acceptance if the technique 
is demonstrated to work. 
 
Vancomycin has been chosen as the type of antibiotic for this study because of its proven track 
record in the spine literature 97,98,99,100 and because of its efficacy against MRSA which has 
emerged as the most common pathogen encountered in surgical site infection 89.  Additionally, 
there are no concerns regarding inhibition of bone healing or osteogenic cytotoxicity 88 or renal 
toxicity, especially at this relatively low dose for systemic toxicity.   
 
 
2.2 Rationale 
Although there is strong theoretical and promising clinical data regarding the use of local 
antibiotics to reduce infection, it is not yet clear that local Vancomycin powder will perform 
better than treatment without local Vancomycin powder in a rigorous head to head clinical trial. 
It is possible that the theoretical benefits of local antibiotics will not translate into reduced 
infections in fracture patients at risk for increased infection. 
 
2.3 Potential Risks and Benefits  
2.3.1 Potential Risks 
The risks associated with this study primarily concern adverse reactions to the study drugs.  All 
drugs are FDA approved and marketed for a variety of uses. The proposed protocol is of an 


 
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investigational use of the medication Vancomycin powder that is to be placed in the orthopaedic 
surgical wound at the time of closure. There is no intention of the protocol to support a new 
indication for use or significant change in labeling of the drugs; is not intended to support a 
change in advertising for the drugs; will not test a new dosage of the drug, nor is it being used in 
a new clinical population; and the study will be conducted with informed consent and in 
compliance with 21 CFR 312.7 regarding promotion and sale of drugs.  Patients in the study will 
be actively monitored for any adverse reactions. The FDA approved this study with an IND on 
10/31/13 (IND #119891). The study and its investigators will comply with all FDA regulations.  
All attempts will be made to minimize risk to the study volunteers; however every research 
study represents some risk to its volunteers including psychological, legal, social and economic 
risks that could be brought about by accidental release of study information into the public 
domain. These study risks are small, however we will have protocols in place to further 
minimize and monitor these risks based on SOP’s developed at the coordinating center. 
 
Additional theoretical risks inherent to this study involve the use of the local Vancomycin 
powder.  The risk of giving antibiotic powder are increased for participants who have an 
allergy to the drug. In addition, there is increased risk for participants who are susceptible to 
local toxicity to the drug. Neither of these issues was observed in the previous clinical trials 
97,98,99,100.  
A sample package insert for Vancomycin power will be attached with the IRB submission. The 
package insert identifies risks associated with the standard use of Vancomycin powder as an 
IV/Injectable medication. At this time we do not know the risks associated with the current 
proposed delivery mechanism.  
 
Additionally there is the risk that the technique may actually increase the risk of infection 
through some unknown mechanism or create some other as yet unanticipated clinically 
significant problem. 
 
2.3.2 Potential Benefits 
Participation in this study will benefit patients in that they will receive more intense follow-up 
than would be considered standard of care.  At the 6 month visit the patient will be assessed for 
pain, health and general well-being and will undergo a musculoskeletal function assessment in 
addition to their standard clinical evaluation. In addition, further assessments will be conducted 
through the use of the Brief Pain Inventory (BPI), Short Form Musculoskeletal Assessment 
(SMFA), and the Veterans Rand 12 item Health Survey (VR12).   
 
3. STUDY OBJECTIVES 
 
3.1 Primary Objective 
 


 
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To compare the proportion of deep surgical site infections within 6 months in patients treated 
with local Vancomycin powders compared to those treated without local Vancomycin powder 
 
3.2 Secondary Objectives 
 
To compare antibiotic sensitivities of the bacteria in the patients who develop surgical site 
infections in study patients treated with local Vancomycin powder compared to those treated 
without local Vancomycin powder. 
 
To build and validate a risk prediction model for the development of surgical site infections in 
patients treated without local Vancomycin powders.  Further, to explore whether the effect of 
local Vancomycin powder is modified by the predicted risk of infection. 
 
3.3 Exploratory Objectives 
N/A 
 
 
4.  STUDY OVERVIEW 
 
The study design is a prospective, randomized controlled trial comparing deep surgical site 
infection rates with and without the use of local Vancomycin powder at the time of fracture 
fixation.  This study design will provide the highest quality evidence to investigate our 
hypothesis that the use of local Vancomycin powder will be effective at decreasing deep surgical 
site infection in these at-risk patients. The study population will be patients aged 18 to 80 years 
of age with high energy fractures to the tibial plateau, or pilon, treated operatively with plate and 
screw fixation.    
 
Patients will be approached for informed consent as soon as is feasible following determination 
of eligibility. During the index hospitalization, participants will be asked to provide basic 
demographic information, health status and function prior to injury. Study injury characteristics 
will be obtained from the surgeon and the participant’s medical record. 
 
Participants will be prospectively followed at 2 weeks, 3, and 6 months post-injury. All follow-
up visits will occur in person at the hospital and consist of both a clinical examination and 
interview.  
 
5. STUDY POPULATION 
 
5.1 Description of the Study Population  
 
Approximately 1000 participants (500 per treatment arm, see power analysis section below) will 
be enrolled from METRC trauma centers over a 12-month period. Participants will be recruited 


 
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during hospitalization for the initial injury.  Consenting procedures are described in detail in 
Sections 8 and 13 of this protocol. 
 
5.1.1 Participant Inclusion Criteria 
Inclusion criteria  
1.   All “high energy” tibial plateau fractures treated operatively with plate and screw fixation. 
We define “high energy” tibial plateau fractures as patients who are either: 
1.1 Initially treated with an external fixation (with or without limited internal fixation) 
and treated definitively more than 3 days later after swelling has resolved. 
1.2 Any type I, II, or IIIA open fracture, regardless of timing of definitive treatment. 
1.3 Any tibial plateau fracture associated with ipsilateral leg compartment syndrome 
fasciotomy wounds. 
 
2.   All “high energy” pilon (distal tibial plafond) fractures treated operatively with plate and 
screw fixation. We define “high energy” tibial plateau fractures as patients who are 
either: 
2.1 Initially treated with an external fixation (with or without fibula fixation or 
limited internal fixation) and treated definitively more than 3 days later after 
swelling has resolved. 
2.2 Any type I, II, or IIIA open fracture, regardless of timing of definitive treatment. 
2.3 Any tibial pilon fracture associated with ipsilateral leg compartment syndrome 
fasciotomy wounds. 
 
3.   Ages 18 to 80 years 
4.   Patients may have co-existing non-tibial infection, with or without antibiotic treatment. 
5.   Patients may have risk factors for infection including diabetes, immunosuppression 
from steroids or other medications, HIV, or other infections. 
6.   Patients may have a head injury 
7.   Patients may have a portion of the fixation (e.g. fibula fixation in pilon or percutaneous 
screws across a tibial plateau fracture) prior to definitive plate fixation, at the initial 
surgery before randomization. 
8. Patients may have other orthopedic and non-orthpaedic injuries. 
9. Patients may have pre-existing musculoskeletal injuries, be non ambulators, or have spinal 
cord injuries. 
10. Women and minorities are included.  
 
Exclusion criteria  
1.  The study injury: tibial plateau, or pilon already infected at time of study enrollment. 
2.   Patient speaks neither English nor Spanish. 
3.   Patients who have already had definitive fixation prior to enrollment in the study. 
4.   Severe problems with maintaining follow-up (e.g. patients who are homeless at the time of 


 
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injury or those how are intellectually challenged without adequate family support) 
5.   Patient allergy, drug administration reaction, or other sensitivities to Vancomycin (such as a 
history of Redman’s Syndrome) 
6.   Pregnancy 
7.   The study injury is type IIIB or IIIC open fractures 
 
 
5.1.3 Co-Enrollment Guidelines 
Patients may be co-enrolled in other observational studies as long as this is consistent with local 
IRB policies. At METRC sites that are participating in the local Vancomycin powder study, 
patients should be preferentially enrolled in the PAIN study if they are eligible for both studies. 
If a patient is not eligible for the VANCO or PAIN studies, they may be enrolled into the 
Oxygen study.  
 
5.2 Strategies for Recruitment  
N/A 
 
6. STUDY PROCEDURES 
 
6.1 Screening and Enrollment 
 
6.1.1 Screening 
 
The study population will include patients between the ages of 18 and 80, with high energy 
fractures to the tibial plateau or pilon, treated operatively with plate and screw fixation will be 
screened for eligibility at each site by the local Research Coordinator in close collaboration with 
the surgeon investigators.  Screening will typically occur during the initial hospitalization for the 
study injury. A screening CRF will be completed on every potentially eligible participant and 
entered into REDCap, the METRC electronic data capture system in order to document screen 
failures.  The study PI and MCC team will be available via email and phone to answer questions 
regarding study eligibility. Contact information for the PI and alternate contact is available in 
Appendix A.  
 
6.1.2 Consent and Enrollment 
 
A prototype consent has been prepared for the local Vancomycin powder study and is attached in 
Appendix D. Individual sites may add material but may not delete material thought to be 
necessary for informed consent. Clinical sites may reformat and reword information to conform 
to their local requirements. The consent form will describe the purpose of the study, the 
procedures to be followed, and the risks and benefits of participation. Copies of the signed 


 
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consent forms will be given to the patient, and this fact will be documented in the patient’s 
record.  
 
Once eligibility has been confirmed, the informed consent process will be completed by the 
Research Coordinator and the attending surgeon.  Patients will be approached about potential 
participation in the study as soon as is feasible following determination of eligibility.  
 
Participants will be approached and given the opportunity to enroll during their initial injury 
treatment. For the high energy tibial plateau and pilon fractures, the definitive treatment is 
typically delayed for roughly 1-2 weeks to allow swelling at the surgical site to resolve before 
proceeding for definitive fixation.  This allows significant opportunity to enroll the patient during 
this window.  Patients often will have time to discuss the study with others prior to making a 
final decision to participate. Patients and their families will be provided with a pamphlet 
describing the study, the risks and benefits of participation and what will be expected of them if 
they choose to participate.  Consent will be obtained in accordance with principles of GCP and 
ICH guidelines. 
 
For the rare case with an open fracture type that the surgeon deems the wound is clean enough 
for definitive fixation at the time of initial treatment, the patient may still be enrolled in the 
study.  These patients will be enrolled at the time of initial trauma. This patient group represents 
a small fraction of the open fractures, which themselves are a small subset of the overall group.    
At high energy trauma centers such as those participating in the study, some percentage of the 
patients will be eligible for the study but will not be able to consent due to traumatic brain 
injuries, intubation, or for other reasons related to their injury.  We will consent these patients 
using the individuals’ legally authorized representative.  The process for obtaining consent for 
surgery or study participation varies based upon the state the patient is being treated within, and 
as such the details of this process will be guided by the standard practice of the local IRB. 
 
All study materials will be provided in both English and Spanish.  
 
Following completion of informed consent, the participant information will be entered into 
REDCap where a study number will be assigned and final eligibility criteria confirmed. 
 
6.1.3 Assessing Capacity to Consent and Consenting a Proxy Respondent 
 
By virtue of the types of injuries studied (resulting from high energy mechanisms such as high 
speed motor vehicle crashes, high falls, and blast injuries) it is expected that a large proportion (> 
15%) to have an associated traumatic brain injury which my render them unable to provide 
consent for the study.  It will be important not to exclude these patients from the study, as it 
would significantly reduce our ability to produce generalizable knowledge. These patients are at 


 
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no greater risk of adverse consequences by virtue of their participation in the study, and should 
be given the same opportunity to participate.    
 
Whenever possible, the patient him or herself (as opposed to a proxy) should be consented. Prior 
to initiating the consent process, the Research Coordinator will contact the patient’s Physician 
for confirmation that the patient has the ability to understand the relevant study information and 
communicate and maintain a choice.  If the physician indicates that the patient lacks the capacity 
to consent the legally authorized representative (LAR) will be contacted. 
 
The research staff will endeavor to answer all questions posed by the patient and his/her family 
to ensure their understanding of the protocol. A limited number of questions will be asked of all 
patients after they are introduced to the study and have reviewed the consent form. These 
questions assess the person’s understanding of the study and what it means to participate, their 
appreciation of the consequences of participation, and their ability to consider alternatives to 
participation. A formal comprehension test may be utilized, or comprehension will be assessed 
by the person(s) obtaining the consent. A template for a comprehension test is provided in 
Appendix E. 
 
The Research Coordinator will ask the questions and determine the appropriateness of the 
responses.  If the Research Coordinator is at all unsure about the patient’s ability to consent s/he 
will consult with the study site PI.    
 
A legally authorized representative (LAR) with reasonable knowledge of the potential participant 
will be approached to consent on the patient’s behalf if one of the following is true: 
• The patient is unresponsive (and likely to remain unresponsive during the study).  
• The patient cannot adequately answer at least 2 questions and it is determined that the 
patient’s level of cognition is not likely to change before surgery.    
 
The choice of LAR will follow standard procedures. The following with be approached in this 
order of priority: 
• Legal guardian  
• Proxy (health care agent) named in an advance directive or durable power of attorney for 
health care; 
• Family member or other surrogate identified by the state law on health care decisions.  
 
Guidance will be provided to assist the LAR in making the consent decision.  They will advised 
to base the decision on the participant’s expressed wishes, or, if these are not known, what they 
believe the participant would have desired under the circumstances of the injury, their beliefs and 
values. If the LAR does not know what the participant would have wanted, the LAR will advised 
to base the decision with the participant’s best interest in mind.  They will be asked to carefully 


 
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consider how much leeway the participant would likely give the LAR in making the choice about 
participation in the study. 
Recognizing that consent is an ongoing process, the study team will encourage the participants to 
ask additional questions that may arise during the course of their participation in the study. 
 
 
6.2 Baseline Data Collection 
 
Once consented into the study, baseline data regarding participant characteristics, injury 
characteristics, fracture classification and medical history/co-morbidities will be collected and 
entered into the REDCap data collection system.  Characteristics about hospital course and 
treatment received will also be collected.  A brief interview will be conducted with the 
participant or his/her surrogate. 
 
Blood sampling across the study will occur as performed at all institutions with respect to 
standard clinical care per institutional practice. This typically includes pregnancy tests when 
appropriate, serum creatinine, and complete blood count at baseline. The labs may or may not 
include tests for fungi. We will also pilot test Vancomycin levels within 24 hours of placement 
of Vancomycin powder in the operating room for the first 30 participants at the main study 
institution, the University of Maryland, Baltimore (PI site to which this FDA approval was 
given). As discussed in more detail in section 7 below, it is anticipated that the system levels will 
be undectable or clinically insignificant based on prior literature 98.  Any adverse events 
identified over these samples will be reported to the IRB, the FDA, and the rest of the 
participating sites. These data will be collected in RedCap and will be reviewed as indicated, by 
the medical monitor (identified below) for the study.  
 
All labs drawn at the sites will follow each institutions standard of care procedures.  We will not 
utilize a central laboratory for testing in this study. We will, however, request CAP/CLIA 
information for all participating sites to ensure that each lab attests to adhering to standard 
testing methodology. 
 
To comply with the FDA Annual Reporting requirements, and because the METRC 
Coordinating Center will not be providing the vials of vancomycin powder to clinical sites, we 
will also collect the name, strength, manufacturer and back number for every vial of vancomycin 
used in this study.  
 
6.2.1 Medical Record Review 
 
• Circumstances and Type of Injury 
• Other Injuries 


 
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• Mode of Transport 
• Length of time in ICU 
• Discharge Disposition 
• Antibiotic Use 
 
6.2.2 Clinical Assessment 
 
• Side of Injury (R/L) 
• AO/OTA Classification  
• Gustilo Type 
• Tscherne Classification  
• AP and Lateral x rays 
 
6.2.3 Participant Interview 
• Medications taken prior to Injury 
• Co-morbidities 
• Health Insurance 
• Height and Weight 
• Demographics (age, gender, race/ethnicity, education) 
• Income 
• Usual Major Activities Before Injury 
• Job Characteristics 
• Current Military Service 
• Job Motivation 
• Smoking History 
• Previous Injuries and Pain 
• Marital Status and Social Support 
 
6.3 Participant Follow up and Data Collection 
 
6.3.1  Follow-up Visit Schedule 
 
Participants will return for follow-up visits at 2 weeks, 3, and 6 months. The two-week visit will 
be determined using the date of definitive fixation. Participants will be expected to begin follow 
up 2 weeks post-definitive surgical fixation for their study injury.  At each follow up visit, 
participants will undergo a clinical evaluation by the treating surgeon and be interviewed by the 
Research Coordinator. 
Each visit will have an interval of time surrounding the ideal date for the visit during which the 
visit may be completed and the data included in the trial database as defined per METRC 
standard operating procedures.   


 
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6.3.2   Clinical Assessments 
 
• Diagnosis of infection and detailed assessment of evidence of infection 
• Complications (type, severity, treatment) 
• Wound Healing 
• Antibiotic Use 
• Fracture Healing 
• Pain 
 
6.3.3   Participant Interviews 
 
• Re-Hospitalizations 
• Self reported pain (6 months only) 
• Brief Pain Inventory (6 months only) 
• Health Related Quality of Life (VR-12) (6 months only) 
• Short Musculoskeletal Function Assessment (SMFA) (6 months only) 
 
6.3.4  Retention  
 
Every effort will be made to retain participants in the study.  The study participants will receive 
an honorarium in recognition of their time and effort.  $50 will be given for completing the 6 
month visits in appreciation for their time and effort.  We will also keep participants engaged 
through use of study updates on the METRC webpage and distribution of follow-up reminders 
and trinkets imprinted with the study logo. 
 
6.3.5  Final Study Visit   
 
Participants will complete the study at month 6. This final visit will occur in the clinic and will 
include the patient interviews and clinical assessments as identified above.  
 
Any ongoing SAEs will be followed to resolution.  
 
6.3.6 Early Termination Visit 
 
Should a participant terminate the study prematurely, if at all possible, all procedures required at 
the 6 month visit will be performed at his/her final visit. 
 
6.4  Study Endpoints 
 


 
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6.4.1 Primary Endpoint 
 
The primary endpoint will be the presence of clinically significant surgical site infection (SSI) in 
the first 26 weeks after surgery, as determined by CDC guidelines 24,34,51.  These guidelines are 
described above in detail related to study outcomes.  
Wound characteristics will also be evaluated using the ASEPSIS score 15,16,84,85. This system has 
also been previously described.  
For each patient who is determined to have an infection, the treatment will also be recorded.  We 
will define deep infections as those that require operative treatment, and superficial infections as 
those that are treated without operative intervention.   
6.4.2 Secondary Endpoints   
Secondary endpoints include culture data in the group that becomes infected.  All deep surgical 
site infections will have sterile intraoperative wound cultures taken, as is currently performed in 
routine clinical practice.  Sensitivities of the isolated bacteria, which are also determined 
routinely in current clinical practice, will be recorded for analysis.  We will describe the type of 
antibiotic resistance experienced in both groups as described in the outcomes measures described 
in the protocol summary.   
 
7. STUDY TREATMENTS 
 
In extremity wounds, a typical local dose would be 1000 mg of Vancomycin powder placed into 
the wound at time of closure.  All other components of the surgery would be per routine protocol 
at the sites. Previous data indicates that the systemic load from this amount will likely be very 
low 97,98,99,100.  The typical IV dose is 1000mg twice a day (often for 6 or more weeks if the 
patient has an infection), so this one time local dose is a relatively small amount of the drug 
compared to what is typically used in systemic IV therapy. 
 
Most orthopaedic trauma surgeons are already familiar with using sterile Vancomycin powder in 
the operating room as it is used to make antibiotic beads and nails.  The powder comes sterile 
and the hospitals are very familiar with storage, handling and all other aspects of managing the 
device.  The dose used for this study will be (1000mg) placed right before wound closure. 
 
Both groups will otherwise receive standard care, including prophylactic intravenous antibiotics, 


 
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and all other aspects of care that are currently standard for each surgeon and anesthesiologist at 
each institution.  Intravenous Vancomycin can be given as IV prophylaxis if that is the center’s 
protocol for an individual patient.  After consultation with multiple infectious disease specialists 
it appears the risk of renal (or other) toxicity from simultaneous IV and local powder application 
of Vancomycin is extremely unlikely.  Prior studies on systemic levels when using local 
Vancomycin powder demonstrated an undetectable level in 80% of the patients, and a low level 
(average 1.6 µg/ml) in 20% of the patients 98. Local application of Vancomycin powder is very 
unlikely to increase the risk of Vancomycin side effects. Additionally, in current clinical practice 
much larger doses of local Vancomycin powder are placed in beads repeatedly during serial 
irrigation and debridements while patients receives IV Vancomycin for weeks at a time without 
any known consequence. In this group, serum levels of Vancomycin are also in the low range 103. 
For these reasons, the study allows the use of Vancomycin for prophylaxis if that is a center’s 
practice.  Whatever antibiotic prophylaxis protocol is used at the site, it should be applied 
consistently in both the treatment and control group. It would not be appropriate to change the IV 
prophylaxis choice based on which treatment group that patient was assigned. No changes should 
be made to routine care based on allocation to the treatment or control group.  
 
Treatment Crossover 
 
Cross-over from one treatment arm to another should be very rare.  Cross-over should only 
occur if for some reason the surgical team determined the local Vancomycin powder could not 
be placed or if the Vancomycin powder is not available to be placed, both of which would be 
extremely unusual.  As patients will not know which treatment group they are in prior to 
surgery, there is no chance that they will elect to switch groups based on the outcome of the 
randomization.  The only likely crossover is study error where an investigator forgets to place 
the local Vancomycin powder in a patient assigned to the treatment group.  The rate of this 
occurrence should be very low. 
 
7.1 Study Treatment #1 
 
7.1.1 Description of treatment   
 
 
Treatment Group (Local Vancomycin Powder):  
 
Participants in the treatment group will receive a maximum dose of 1000mg of Vancomycin 
powder in their wound bed, which is placed right before wound closure. Vancomycin powder 
may be combined with normal saline as per clinical practice at the participating institution.  


 
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In addition, participants in this group will receive standard of care treatment for their injury, to 
include all institution specific standard treatment (prophylactic and otherwise) for preventing 
and treating infection.  
 
7.1.2 Potential Risks and/or adverse effects  
 
The risks of giving antibiotic powder are increased for participants who have a known allergy to 
the drug. In addition, there is increased risk for participants who are susceptible to local toxicity 
to the drug. Additionally there is the risk that the technique may actually increase the risk of 
infection through some unknown mechanism or create some other as yet unanticipated clinically 
significant problem. 
 
The typical risks of any fracture surgery include bleeding, infection, malunion, nonunion, and 
neurovascular injury are inherent risks the operative procedures involved and do not differ from 
the standard of care. 
Any time information is collected for a study there is a small risk of breach of confidentiality. 
However, this risk is not greater than the risk that already exists in clinical settings when 
handling medical data.  
 
 
7.2 Study Treatment #2 
 
7.2.1 Description of treatment   
 
Control Group (Standard of Care): 
Participants in this group will receive standard of care treatment for their injury, to include all 
institution specific standard treatment (prophylactic and otherwise) for preventing and treating 
infection. Participants in this group will not receive local Vancomycin powder.  
 
7.2.2 Potential Risks and/or adverse effects  
 


 
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The typical risks of any fracture surgery include bleeding, infection, malunion, nonunion, and 
neurovascular injury are inherent risks the operative procedures involved and do not differ from 
the standard of care. 
Any time information is collected for a study there is a small risk of breach of confidentiality. 
However, this risk is not greater than the risk that already exists in clinical settings when 
handling medical data.  
 
 
8. ASSESSMENT OF SAFETY 
 
The study will monitor and report adverse events to ensure patient safety. Definitions and 
procedures for reporting adverse events are designed to satisfy 45 CFR Part 46, Subpart A; the 
“Common Rule”, shared by 17 Departments and Agencies as well as 21 CFR 312, the FDA 
regulation for adverse events.  The Common Rule requires written procedures and policies for 
ensuring reporting of “unanticipated problems” involving risks to participants to IRBs, 
appropriate institutional officials, and the Department or Agency Head.  
 
The medical monitor (MM) is responsible for providing medical guidance and overseeing patient 
safety for the study. The MM participates in determining the course of action necessary to meet 
safety goals and objectives.  This is achieved through the review of Serious Adverse Event 
reports; resolving safety issues; and interacting with Principal Investigators. 
Each participating site is responsible for ensuring that all local IRB requirements for reporting 
adverse events (both internal and external) are met.   
 
8.1 Definitions 
 
8.1.1 Adverse event 
 
Any untoward or unfavorable medical occurrence in a human subject, including abnormal sign 
(e.g., abnormal physical exam or laboratory finding), symptom or disease temporally associated 
with the subject’s participation in the study, whether or not considered related to the subject’s 
participation.  
 
8.1.2 Unanticipated problem 
 
Any incident, experience, or outcome that meets all of the following criteria: 
(1) is unexpected, in terms of nature, severity, or frequency, given the research procedures 
that are described in the protocol and informed consent document and the characteristics 
of the patients eligible for the study. 
 


 
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(2) is related or possibly related to treatment/procedures under study; possibly related 
means there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the study procedures or treatments. 
 
(3) suggests that the participation in the study may place subjects or others at a greater 
risk of harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Please note that not all adverse events are unanticipated problems and only some unanticipated 
problems are in fact adverse events.  For instance, if a laptop containing study data is stolen, this 
is an unanticipated problem but it is not an adverse event since it is not an untoward or 
unfavorable medical occurrence in a human subject 
 
8.1.3 Serious Adverse Event 
 
A serious adverse event is defined as: 
1. Death 
2. Allergic or other reaction that is thought to be due to the 
Vancomycin powder 
3. Other events that are unexpected AND serious AND related or 
possibly related to the use of Vancomycin for the study 
 
8.2 Methods and Timing for Assessing, Recording, and Analyzing, Managing Safety 
Parameters 
8.2.1 Methods and Timing of Assessment  
 
Adverse events may be discovered during regularly scheduled visits or through unscheduled 
patient contacts between visits.  Adverse events related to study procedures will be assessed 
during the index hospitalization and at each study visit.  They will be recorded on study data 
forms whether or not they are thought to be associated with the study. 
 
8.2.2 AE/SAE Grading and Relationship Assignment 
 
Adverse event grading:  Adverse events will be graded using standard criteria. Relationship of 
event to the study procedure will be determined by the study physician.  
GRADE 1 (Mild) Transient or mild discomfort (< 48 hours); no medical intervention/therapy 
required 
 
 
 
GRADE 2 (Moderate) Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required 
 
 


 
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GRADE 3 (Severe) Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible 
 
GRADE 4 (Life-threatening) Extreme limitation in activity, significant assistance required;   
significant medical intervention/therapy required, hospitalization or hospice care probable. 
 
Relationship Assignment The relationship of the adverse event to participation in the study will 
be assessed as either:  
 
 
Definitely related  
Probably related 
Possibly related 
Unlikely related 
Unrelated    
 
 
8.2.3 Recording and Documentation  
 
Sites will maintain source documents including but not limited to (laboratory and radiology 
reports, clinical notes and discharge summaries). After review of initial and final reports by the 
medical monitor, the events may be reclassified at their discretion. 
 
8.2.4. Management of Adverse Events 
 
Adverse Events and Serious Adverse Events will be managed according to protocol guidelines. If 
specific guidelines do not exist, AEs/SAEs will be managed according to the medical judgment 
of the treating physician. 
 
8.3 Adverse Event Reporting Procedures 
 
8.3.1 Local Reporting Requirements.  
 
 
Study sites must always follow and comply with their own local institution’s adverse event 
reporting requirements, which may differ from those adopted by the local Vancomycin powder 
Study. Depending on the local requirements, a site may report events locally and not report those 
events to the METRC Coordinating Center. Each participating site is responsible for ensuring 
that all local IRB requirements for reporting adverse events (both internal and external) are met.   
 
8.3.2 SAE and Unanticipated Problem Reporting Requirements 
 
All Serious Adverse Events that are Unexpected AND related or possibly related to the study 
must be reported to the Medical Monitor and METRC Coordinating Center within 72 hours of 


 
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being made aware of the event. In addition, all SAEs related to use of study medications would 
be reported to the individual manufacturers to contribute safety data for these drugs, as well as to 
the FDA via the MedWatch voluntary reporting mechanism using form FDA 3500. 
 
In addition, Unanticipated Problems (UPs) that are not adverse events must also be reported to 
the METRC Coordinating Center within 14 calendar days after the event has been discovered.    
SAEs/UPs will be reported to the METRC Coordinating Center by entering the SAE/UP form 
into REDCAP. REDCap is programmed to automatically send an email to the Coordinating 
Center for both SAEs and Ups, and to the Medical Monitor in the case of an SAE.  
 
The Medical Monitor for this study is: 
Mark Swiontkowski, MD, FACS 
Department of Orthopedic Surgery 
2450 Riverside Ave., R200 
Minneapolis, MN 55454 
Telephone: (612) 273-7951     
Fax: (612) 273-7959 
E-mail: swion001@umn.edu  
 
 
8.3.3 METRC Coordinating Center Reporting Responsibilities  
 
As appropriate and per METRC policies, the Coordinating Center will send a copy of each report 
received about an event judged reportable to all clinical sites, with instructions for each to 
forward the report to their IRB.  
 
Copies of the report will also be sent to the DoD, the Study PI, and to the Medical Monitor. The 
MCC will maintain a list of such events for reporting and review at Steering Committee 
meetings. 
 
8.3.4 Department of Defense Reporting Requirements 
 
The following are reporting requirements and responsibilities of the Principal Investigator to the 
United States Army Medical Research and Materiel Command’s (USAMRMC) Office of 
Research Protections (ORP), Human Research Protection Office (HRPO). 
        (1)  The protocol will be conducted in accordance with the protocol submitted to and 
approved by the USAMRMC ORP HRPO and will not be initiated until written 
notification of approval of the research project is issued by the USAMRMC ORP 
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        (2)  Accurate and complete study records will be maintained and made available to 
representatives of the U.S. Army Medical Research and Materiel Command as a part 
of their responsibility to protect human subjects in research.  Research records will be 
stored in a confidential manner so as to protect the confidentiality of subject 
information.   
        (3)  All unanticipated problems involving risk to subjects or others, serious adverse events 
related to participation in the study and subject deaths related to participation in the 
study will be promptly reported by phone (301-619-2165), by email 
(hsrrb@.amedd.army.mil), or by facsimile (301-619-7803) to the USAMRMC, Office 
of Research Protections, Human Research Protection Office.  A complete written 
report will follow the initial notification.  In addition to the methods above, the 
complete report will be sent to the U.S. Army Medical Research and Materiel 
Command, ATTN: MCMR-RP, 504 Scott Street, Fort Detrick, Maryland 21702-5012.   
        (4)  Suspensions, clinical holds (voluntary or involuntary), or terminations of this research 
by the IRB, the institution, the Sponsor, or regulatory agencies will be promptly 
reported to the USAMRMC ORP HRPO. 
        (5)  Any deviation to the protocol that may have an adverse effect on the safety or rights of 
the subject or the integrity of the study will be reported to the USAMRMC ORP 
HRPO as soon as the deviation is identified.   
        (6)  Major modifications to the research protocol and any modifications that could 
potentially increase risk to subjects will be submitted to the USAMRMC ORP HRPO 
for approval prior to implementation.  All other amendments will be submitted with 
the continuing review report to the USAMRMC ORP HRPO for acceptance. 
        (7)  A copy of the approved continuing review report and the local IRB approval 
notification will be submitted to the USAMRMC ORP HRPO as soon as these 
documents become available.  A copy of the approved final study report and local IRB 
approval notification will be submitted to the USAMRMC ORP HRPO as soon as these 
documents become available.   
        (8)  The knowledge of any pending compliance inspection/visit by the FDA, OHRP, or 
other government agency concerning this clinical investigation or research, the issuance 
of Inspection Reports, FDA Form 483, warning letters or actions taken by any 
Regulatory Agencies including legal or medical actions and any instances of serious or 
continuing noncompliance with the regulations or requirements that relate to this 
clinical investigation or research will be reported immediately to USAMRMC ORP 
HRPO.   
 
Unanticipated problems involving risk to volunteers or others, serious, unexpected adverse 
events related to participation in the study and all volunteer deaths related to participation in the 
study will be promptly reported by phone (301-619-2165), by e-mail (hsrrb@amedd.army.mil), 
or by facsimile (301-619-7803) to the U.S. Army Medical Research and Materiel Command’s 
Office of Research Protections, Human Research Protections Office.  A complete written report 
will follow the initial notification.  In addition to the methods above, the complete report will be 


 
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sent to the U.S. Army Medical Research and Materiel Command, ATTN:  MCMR-RPH, 504 
Scott Street, Fort Detrick, Maryland  21702-5012 
 
8.4 Reporting Pregnancy  
N/A 
 
8.5 Type and Duration of the Follow-up of Participants After Adverse Events 
 
Study patients who experience an SAE will be followed until resolution of the event, and a final 
report will be submitted to the medical monitor, the FDA, and the coordinating center. 
 
8.6 Modifications of Study Agent(s)/Intervention(s) for a Participant  
N/A 
8.7 Halting Rules for the Protocol  
 
If the treating surgeon determines that the patient is medically contraindicated to receiving the 
Vancomycin powder for any reason, they should treat the patient appropriately and not pursue 
the application of the study specific treatment arm. 
8.8 Stopping Rules for an Individual Participant/Cohort 
 
The DSMB will review the overall progress of the trial in terms of recruitment and data quality 
and makes a formal recommendation to the DOD at the end of each scheduled meeting as to 
whether the trial should continue unmodified, continue with protocol modifications or be 
stopped. 
 
8.9 Premature Withdrawal of a Participant 
 
Withdrawal from the study will be overseen by both the Coordinating Center, and individual 
institution to which the participant is enrolled. However, once surgery has been completed; the 
treatment arm of the study will be final so it is not possible for the subject to withdraw from 
this portion of the study.  However, the patient could withdraw from the study by failing to 
follow- up.  In the event that participants fail to follow up, research staff will attempt to contact 
them to determine whether or not they are having problems. If participants choose to withdraw 
after they have received treatment they will be made aware that this choice will not affect their 
current and future care at the study site but they will be asked to communicate with the study 
team any issues they might have related to their initial injury. Patients will not be removed for 
failure to follow post-operative instructions, non-compliance with treating instructions, or any 
other deviations from ideal clinical pathway. These deviations are common in clinical 
medicine and therefore are not grounds for removal from the study. 
 


 
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Only loss of funding or behavior by the patient (e.g. threatening of clinical staff) would cause 
termination of the clinical relationship would require withdrawal from the protocol.  Neither 
is anticipated to be common but participants will be made aware that termination could occur 
and that the research team will communicate any changes associated with the study that may 
affect them and their participation. If study termination needs to occur due to loss of funding, 
all participants currently enrolled will be followed to completion and no new participants 
would be enrolled. Communication of this would occur to the satellite sites via the 
coordinating center. 
 
8.10 Replacement of a Participant Who Discontinues Study Treatment  
N/A 
 
9. MONITORING  
 
9.1 Site Monitoring Plan 
 
The METRC Coordinating Center will be responsible for site monitoring consistent with 
ICH/FDA guidelines. Monitoring will include a combination of remote and on-site visits of 
participating clinical research sites to review the individual subject records, including consent 
forms, case report forms, supporting data, laboratory specimen records, and medical records 
(physicians’ progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection of 
study subjects, compliance with the protocol, and accuracy and completeness of records. The 
monitors also will inspect sites’ regulatory files to ensure that regulatory requirements are being 
followed.  
 
The site PI will make study documents (e.g., consent forms, case report forms) and pertinent 
hospital or clinic records readily available for inspection by the local IRB, the site monitors, the 
DOD, the Office for Human Research Protections (OHRP), or other regulatory authorities for 
confirmation of the study data. 
 
9.2 Safety Monitoring Plan 
 
9.2.1 Safety Review Plan by the DSMB 
 
An independent Data and Safety Monitoring Board (DSMB), appointed by DOD, is responsible 
for monitoring the accumulated interim data as the trial progresses to ensure patient safety and to 
review efficacy, evaluate recruitment, and assess overall data quality.  An interim analysis will 
occur after 33% of patients have been followed for 6 months. 
 
The DSMB is a multidisciplinary group with a written charge provided by METRC and DOD.  
The DSMB will meet in person to review the protocol.  After the trial commences, the DSMB 


 
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meets twice a year to review data or other issues.  The DSMB may request more frequent 
meetings if necessary to fulfill it charge.  It may also request additional safety reports on a more 
frequent basis.   For example, all serious adverse events (SAE) are reported to the DSMB for 
their consideration and recommendations as they occur. 
 
At its first meeting the DSMB will review definition of all outcomes, adverse events and serious 
adverse events and revisions to the protocol made as appropriate. Summary data on adverse 
events (together with study outcomes) will be monitored by the DSMB at its semiannual 
meetings or more frequently, as needed. These summaries will include analyses comparing rates 
of adverse events by blinded treatment group, by clinic, or in other subgroups requested by the 
DSMB. 
 
After each meeting, the DSMB will issue a written summary of its review of the study data, 
including adverse events, for transmission to the IRBs at each of the study centers. Analyses or 
listings of adverse events will not be provided to the IRBs; however, adverse events involving 
unanticipated problems involving risks to participants, or breaches of protocol, which might 
entail risk to participants, must be reported to local IRBs as soon as possible after they are 
discovered. Each participating center is responsible for ensuring that all local IRB requirements 
for reporting adverse events are met. 
 
The DSMB will review semi-annual reports by masked treatment groups of the primary and 
secondary outcomes as well as all adverse events that are not identified as outcomes per se.  
Interim data on safety measures requested by the DSMB are reviewed at each of the scheduled 
semi-annual full meetings.  Analyses will be prepared comparing rates of adverse events by 
treatment group, by clinical center or by other subgroups as requested by the DSMB.  Serious 
adverse events will be reviewed by the DSMB as they occur with the option of a teleconference 
if any DSMB member requests 
 
 
10. STATISTICAL CONSIDERATIONS 
 
10.1 Overview and Study Objectives 
Again, the primary objective of the study is to investigate if local Vancomycin powder reduces 
deep surgical site infection after operative treatment of fractures at risk for surgical site infection, 
as this is a common problem encountered in the treatment of military injuries. The study design 
is a prospective, randomized controlled trial comparing deep surgical site infection rates with and 
without the use of local Vancomycin powder at the time of fracture fixation. The study 
population will be patients aged 18 to 80 years of age with high energy fractures to the tibial 
plateau or pilon, treated operatively with plate and screw fixation.    
 


 
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10.2 Sample Size Considerations  
We based the sample size on a two-group comparison of proportion of deep surgical site 
infection between the treatment groups during the first 6 months of treatment. In our prior 
oxygen study, 250 patients draw from a similar patient population as that proposed yielded a 3-
month deep infection risk of 11.5% 72.  As discussed in section 1.5, rates of deep surgical site 
infection after these fractures has varied considerably in previous studies with both higher and 
lower rates being reported in what are typically retrospective studies.  We argue that our existing 
prospective data in an almost identical patient population, with the same fracture types, using the 
same primary outcome measure should yield a reasonably accurate estimate of anticipated 
infection rate in the proposed study group.  
Therefore, in our sample size calculations, we assumed that control arm would have an infection 
probability of 11%. Using a two-sided test 0.05 level test of no treatment difference, we need 
464 patients to have 80% power to detect a 5.1% absolute reduction (45% relative reduction) in 
the probability of infection by 6 months.  The previous spine literature has shown much larger 
relative reduction in surgical site infection so this is a conservative estimate in that regard. 
We plan one interim analysis (after a third of the patients have been followed for 6 months) 
using an O’Brien-Fleming stopping boundary.  We inflate the sample size by 1% in order to 
preserve the type I error.  We also conservatively inflate the sample size by 5% to account for 
loss to follow-up.  
 
 
Sample Size 
 
Based on the above considerations, the targeted sample size for the study is 500 fractures per 
study arm.  
 
10.3 Randomization 
 
Randomization Methodology. Patients will be randomized electronically by the online Data 
Management System maintained at the Coordinating Center at Johns Hopkins School of Public 
Health.  Patients will be randomly assigned (within center) in a 1:1 ratio to either treatment 
group (local Vancomycin powder) or control group (no local antibiotics).   Randomization will 
occur at the time of the surgery so that the patient will not be aware pre-operatively or post-
operatively which treatment group he or she is in. 
 
Block randomization will be used to ensure equal distribution of treatment and control patients 
within the two fracture types (tibial plateau, and pilon fractures).  Participants who refuse 
randomization will not be eligible for the study and will receive the control treatment. 


 
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Blinding of Randomization.  Due to the nature of the study it will not be possible to blind 
the treating surgeon regarding which treatment the patient received.  There will be no way to 
examine the patient or the radiographs to determine if the patient received the local 
Vancomycin powder.  As the primary outcome measure is deep surgical site infection 
requiring return to the operating room, we believe that the surgeon’s lack of blinding is less 
problematic in this case compared to an outcome variable that required more subjective 
evaluation such as superficial infection.  Further, a standardized METRC infection CRF was 
designed during this study to record standard data (culture data, wound characteristics) to 
guard against any possibility of false positives. 
 
Additionally, we will blind all of the data from the statistician prior to the preparation of 
reports when blinding is no longer possible, as is the standard practice at the data coordinating 
center at Johns Hopkins School of Public Health.  All analyses will be done at the data 
coordinating center (which is not a clinical center) to help reduce risk of bias in the analysis. 
 
  
10.4 Missing Data and Measures to Minimize Bias 
 
Missing data is a serious concern that complicates the interpretation of the study results.  We will 
address this issue from both a study conduct and analysis perspective.  Regarding study conduct, 
we will: 
1. Limit participant burden and inconvenience in data collection 
2. Select high quality investigators 
3. Provide pre-study training of investigators as well as on-study reinforcement 
4. Reimburse investigators based on follow-ups completed not on per-patient basis. 
5. Monitor and report missing data rates during the study 
6. Emphasize the importance of full participation in the study during the consent 
process. 
7. Collect information on the reasons for missing data. 
8. Actively engage participants and educate them about the importance of participation 
9. Hold regular Protocol Committee meetings to discuss strategies for follow-up    
10. Set targets for acceptable rates of missing data and terminate sites not meeting targets.  
 
As with most prospective studies, missing data will be unavoidable (even with excellent 
follow- up).  Since the informative nature of missing data cannot be verified from the observed 
data, we will adopt a sensitivity analysis framework for reporting results. We will analyze data 
under a variety of modeling assumptions regarding how strongly the missingness mechanism is 
related to outcomes 65. 
 


 
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10.5 Planned Interim Analysis 
 
An independent Data and Safety Monitoring Board (DSMB) is responsible for approval the 
protocol for this trial and for monitoring the accumulated interim data as the trial progresses 
to ensure patient safety, review efficacy, evaluate recruitment, and assess overall data quality. 
After the trial commences, the DSMB will meet twice per year to review data and other trial-
related issues. The DSMB may request more frequent meetings if necessary to fulfill its 
charge. 
The DSMB will review one planned interim analysis of the primary outcome measure.  
O’Brien- Fleming stopping guidelines for efficacy will apply.  The interim analysis will occur 
when approximately 1/3 of the patients (roughly 330) will have 6-month outcome data. At the 
end of each meeting, the DSMB will make a formal recommendation as to whether the trial 
should continue un-modified, continue with protocol modifications, or to be stopped. 
 
10.6 Analysis Plan 
 
Specific Aim 1: 
 
Statistical analyses will follow the intent-to-treat paradigm, which means all patients 
will be analyzed according to the treatment group to which they were randomized. 
Treatment effects for binary endpoints (e.g., infection) will be estimated using a two-
group binomial comparison of proportions; 95% confidence intervals for the absolute 
risk difference and relative risk will be reported.  Tests on the null hypothesis of no 
treatment effect will be based on both a Chi-squared test and a Fisher’s exact test – p-
values will be reported. 
Treatment effects for continuous endpoints will be estimated using a two- group 
comparison of means; 95% confidence intervals for the difference in means will be 
reported.  Tests on the null hypothesis of no treatment effect will be based on both a t-
test and a Wilcoxon rank-sum test and p-values will be reported. 
For both binary and continuous outcomes, regression modeling may be employed if 
concerns about confounding arise, due to imbalances between treatment groups with 
respect to key prognostic baseline covariates. Random effects regression modeling may 
also be employed if concerns regarding the clustering of outcomes within surgeons or 


 
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centers emerge. 
 
Specific Aim 2: 
 
For patients who are infected, we will compute a one-sided, 95% lower confidence interval 
for the difference in antibiotic sensitivity to between treated and control.  We will compare 
this difference to a 10% non-inferiority margin. 
 
Specific Aim 3: 
 
We will build a risk prediction model for infection using data from our previous oxygen trial 
and a training sample from the control group of the proposed trial to estimate the parameters of 
a multivariate logistic regression model. Demographic and injury characteristics will be 
included as covariates in the model. The predictive accuracy of the model will be assessed by 
computing the estimated risk of infection on a test sample of patients from the control group of 
the proposed trial and calculating the area under the receiver operating characteristic curve. 
 
After building the risk prediction model, we will compute a risk prediction score for each 
patient in the trial and assess, via interaction terms in a logistic regression model, whether the 
effect of local Vancomycin powder on infection is modified by risk score. 
 
 
11. QUALITY CONTROL AND QUALITY ASSURANCE  
 
11.1 Data Quality Assurance 
 
Quality Control (Q/C) and Quality Assurance (Q/A) procedures that apply to all studies are 
outlined in the METRC Manual of Operations (MOP).  A certification process (also outlined in 
the MOP) will be used as a basis for training and certification of the study personnel involved in 
data collection.  In addition to consortium wide training and certification procedures, additional 
requirements may be added based on the nature of the study.  Ongoing data edits and audits will 
be performed to ensure collection of quality data. The continuous and timely flow of data from 
the centers to the MCC is an essential prerequisite for maintaining data quality.  
Monthly enrollment reports will be distributed to each center that will summarize recruitment, 
data completion and timeliness of data entry. These reports will also include a set of queries 
generated by REDCap and sites will be asked to address these queries within 10 business days. 
 
11.2 Training and Certification of Centers 
 


 
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All participating centers together with their respective study personnel will undergo certification 
that included training, local site IRB, and a knowledge assessment on the study design and 
procedures.   
 
 
12. ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
12.1 IRB/Ethics Committee 
 
IRB approval will be obtained from the MCC at Johns Hopkins Bloomberg School of Public 
Health, the DoD, and each participating clinical site according to METRC policies and 
procedures. Sites that recruit patients will submit METRC study recruitment materials to their 
organization’s IRB prior to use at that facility. 
Sites must provide the Coordinating Center with a copy of the initial IRB approval notice and 
subsequent renewals as well as copies of the IRB approved consent statements. 
No site can begin work related to this study until the site has been certified by the MCC in 
accordance with METRC policies and procedures. 
 
12.2 Exclusion of Women, Minorities, and Children (Special Populations) 
 
The proposed study anticipates recruiting a significant proportion of racial/ethnic minorities 
(African-Americans, Asian-Americans and Hispanics) as well as non-Hispanic white subjects. 
The study will not include children or prisoners. The study will also exclude pregnant women.  
 
12.3 Participant Confidentiality 
 
It is the investigator’s responsibility to conduct the protocol under the current version of 
Declaration of Helsinki, ICH Guidelines, Good Clinical Practice, and rules of local IRBs. The 
investigator must ensure that the patient’s anonymity be maintained in their data submission to 
the Data Coordinating Center.  
 
Patients will be identified only by an identification code but not by their name, SSN, or hospital 
medical record number. Study Site Investigators will maintain a separate confidential enrollment 
log, which matches identifying codes with the patients’ names and addresses available only to 
local clinic staff certified by the MCC to participate in the study.  
 
All study forms, reports, and other records that are part of the study data collection materials will 
be identified by coded number to maintain patient confidentiality. All paper records will be kept 
in locked file cabinets. All electronic records of study data will be identified by coded number. 
Clinical information will not be released without written permission of the patient, except as 
necessary for monitoring by the sponsor (MCC), IRB, DOD, or DSMB. Consent procedures and 


 
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forms, and the communication, transmission and storage of patient data will comply with 
individual site IRB and DOD requirements for compliance with The Health Insurance Portability 
and Accountability Act (HIPAA). 
 
12.4 Study Discontinuation  
 
Participants will be informed that they may discontinue the study at any time, for any reason. 
They will be assured that the medical care which they receive at the participating facility will not 
be affected should they elect to discontinue participation in the study.  
 
 
13. DATA HANDLING AND RECORD KEEPING 
 
13.1 Data Management Responsibilities 
 
Instructions concerning the recording of study data on case report forms will be provided by the 
MCC. Each study site is responsible for transmitting the data in a timely fashion. 
The research coordinators at each site will obtain the information necessary to complete the case 
report forms (CRFs) from several sources including but not limited to, the patient's medical 
record, clinical evaluations and patient interviews. These forms will NOT contain the patient’s 
name, SSN, or hospital medical record number; they will be identified only by a unique patient-
specific study number.    
 
The Site Research Coordinator will enter non-personally identifiable information into a central 
and secured web-based data management system being implemented for all Consortium studies, 
known as REDCap. This data management system has incorporated state-of-the-art features for 
electronic data collection and is configured in accordance with best practices for information 
technology and research data management.   
 
All research data, in hard copy or electronic form, will be stored and managed in a secure 
manner following applicable federal regulations and ICH guidelines and according to 
institutional policies and practices. Hard copy documents containing subject data, patient 
identifiers and contact information will be stored in secure, locked containers (file cabinets, 
drawers, etc.) in accordance with standard document management practices.  
 
At all times only MCC-certified key personnel specifically designated and authorized by the 
Principal Investigator shall have access to any research related documents, including electronic 
data and medical records.  All such personnel will be properly trained and supervised regarding 
the management and handling of confidential materials. The Principal Investigator assumes full 
responsibility for such training, supervision, and conduct.  This information will be available for 
audit by study monitors and representatives of the local IRB, the MCC, the DOD, and the OHRP. 
 


 
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13.2 Data Capture Methods 
 
Data will be collected in real time by the investigator or study coordinator directly on paper Case  
Report Forms (CRFs), which will serve as source documents for the study. Source documents, 
which will include both the CRFs and other supporting medical records (e.g laboratory & 
radiology reports, clinical notes and discharge summaries), will be signed by PI, other site 
Investigator, or Research Coordinator as indicated in the CRF instructions. The Research 
Coordinator, or MCC-certified staff member working under the supervision of the research 
coordinator, will enter the data from the CRFs into the REDCAP database.  
 
13.3 Types of Data 
 
Data will include medical and surgical histories, laboratory reports (as obtained as part of 
standard clinical care by site), radiology reports, clinical evaluations, adverse events and patient 
interviews.  
 
13.4 Source Documents and Access to Source Data/Documents 
 
Source documents including CRFs, laboratory results (as obtained as part of standard clinical 
care by site), patient surveys, medical records, etc. will be maintained at the site and will be 
made available to study monitors, and representatives of regulatory agencies including the MCC, 
DOD, IRB, and OHRP.  
 
13.5 Study Records Retention 
 
Study records will be maintained in accordance with current ICH guidelines.  Data will be 
maintained for five years following the end of research-related activities.  At the end of this 
period, each site will provide the Coordinating Center a signed verification that these data have 
been destroyed. 
 
 
13.6 Protocol Deviations 
 
Records of protocol deviations will be noted on the Protocol Deviation CRF (AF05) with the 
reason for the deviation recorded, as well as any action taken to mitigate the deviation. This 
information will be entered into REDCap. These records will be provided to the site’s IRB in 
accordance with local reporting requirements and be made available to study monitors. 
 
 
14. PUBLICATIONS POLICY 
Publications will be written in accordance with the METRC publication policy (available on the 
METRC website: www.metrc.org). 


 
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57. O’Toole RV, Castillo RC, Pollak AN, MacKenzie EJ, Bosse MJ and the LEAP Study Group 
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17. APPENDICES 
APPENDIX A: STUDY CONTACT ROSTER 
Principal Investigator (Protocol Chair) 
 
Robert V. O’Toole, MD 
University of Maryland, Baltimore 
Department of Orthopaedic Trauma 
22 S. Greene St.  
Baltimore, MD 21201 
Phone: 410-328-6292 
E mail: rotoole@umoa.umm.edu 
 
 
METRC Coordinating Center Study Principal 
Investigator 
 
Renan Castillo, PhD 
Johns Hopkins Bloomberg School of Public Health 
Dept. Health Policy and Management 
624 N. Broadway Room  
Baltimore MD, 21205 
Phone: 410-614-4024 
Email: rcastill@jhsph.edu 


 
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DOD Program Officer 
 
Joseph C. Wenke, PhD  
Program Manager  
United States Army Institute of Surgical 
Research  
3400 Rawley E. Chambers Avenue, Bldg. 
3611  
Fort Sam Houston TX, 78234-6315  
Phone: 210-916-3742; Cell: 210-288-2431  
Email: Joseph.Wenke@us.army.mil   
 
Medical Monitor 
 
Marc Swiontkowski, MD  
Professor of Orthopaedic Surgery 
University of Minnesota  
2512 South 7th Street 
Suite R200 
Minneapolis, MN 55454 
Phone: (612) 273-,0 
Email: swion001@umn.edu 
 
 
METRC Coordinating Center  
 Director of Protocol Development 
 
Lauren E. Allen, MA 
Johns Hopkins Bloomberg School of Public Health 
Dept. of Health Policy and Management 
415 N. Washington Street 
Baltimore MD, 21231 
Phone: 410-955-2492 
Email: lallen19@jhu.edu  
 
METRC Coordinating Center Study Manager 
 
Tara J. Taylor, MPH 
Dept. of Health Policy and Management 
415 N. Washington Street Baltimore MD, 21205 
Phone: 410-614-6081 
Email: ttaylo56@jhu.edu 
 
METRC Coordinating Center  
Director of Data Management 
 
Anthony Carlini, MS 
Johns Hopkins Bloomberg School of Public Health 
Dept of Health Policy and Management 
415 N. Washington Street Baltimore MD, 21205 
Phone: 410-502-8455 
Email: acarlini@jhu.edu 
 
 
 
 


 
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APPENDIX B: PROTOCOL COMMITTEE 
Robert V. O’Toole, MD (Study PI)  
 
Renan Castillo, PhD  
University of Maryland Medical Center 
 
Johns Hopkins Bloomberg School of Public 
 
 
 
 
 
 
 
Health 
 
Michael Bosse, MD   
 
 
 
Amanda Holmes, MS 
Carolinas Medical Center 
 
 
 
University of Maryland Medical Center 
 
Manjari Joshi, MD  
 
 
 
Daniel Scharfstein, ScD 
University of Maryland Medical Center 
John Hopkins Bloomberg School of Public 
Health 
 
Ellen MacKenzie, PhD 
 
 
 
Lauren E. Allen, MA 
Johns Hopkins Bloomberg School of Public 
Johns Hopkins Bloomberg School of Public  
Health 
Health 
 
David Hak, MD 
 
 
 
 
Tara Taylor, MPH 
Denver Health & Hospital Authority  
Johns Hopkins Bloomberg School of Public 
Health  
 
Daniel Chan, MD  
 
 
 
 
Dean Tsukayama, MD 
 
Florida Orthopaedic Institute/Tampa  
Hennepin County Medical Center  
General & St. Joseph’s Hospitals 
 
Joshua Langford, MD 
Clinton Murray, MD 
Orlando Regional Medical Center 
Brooke Army Medical Center 
 
 
Debra Sietsema, PhD, RN 
Zachary Roberts, MD 
Orthopaedic Associates of Michigan  
 
University of Oklahoma/OU Med Center 
Spectrum Health 
 
 
 
 
 
 
 
 
 
 
 
Hassan Mir, MD 
 
 
 
 
Joseph Hsu, MD 
 
 
 
Vanderbilt University Medical Center 
 
Carolinas Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nalini Rao, MD 
 
 
 
 
Matthew Graves, MD 
 
 
University of Pittsburg 
 
 
 
University of Mississippi 
 
 
 
 
 
 
 
 
 
Study website: www.metrc.org 
 
 
 
 
 
 
 


 
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APPENDIX C: DATA COLLECTION SCHEDULE  
Assessment 
Base-
line 
2 
Week
s 
3mo 
6mo 
Patient Characteristics  
 
 
 
 
Demographics (age, gender, 
race/ethnicity, education) 
X 
 
 
 
Income 
X 
 
 
 
Usual Major Activities Before Injury 
X 
 
 
 
Job Characteristics 
X 
 
 
 
Current Military Service 
X 
 
 
 
Job Motivation 
X 
 
 
 
Smoking History 
X 
 
 
 
Previous Injuries and Pain 
X 
 
 
 
Marital Status and Social Support 
X 
 
 
 
General Injury Characteristics  
 
 
 
 
Circumstances and Type of Injury 
X 
 
 
 
Other Injuries 
X 
 
 
 
Medical History 
 
 
 
 
Medications taken prior to Injury 
X 
 
 
 
Co-morbidities 
X 
 
 
 
Health Insurance 
X 
 
 
 
Height and Weight 
X 
 
 
 
Study Injury Characteristics 
 
 
 
 
Side of Injury 
X 
 
 
 
AO/OTA Classification  
X 
 
 
 
Gustilo Type 
X 
 
 
 
Tscherne Classification  
X 
 
 
 
Muscle Injury 
X 
 
 
 
Nerve Damage 
X 
 
 
 
Soft Tissue Loss 
X 
 
 
 
AP and Lateral x rays 
X 
 
 
 
Index Hospitalization 
 
 
 
 
Mode of Transport 
X 
 
 
 
Length of time in ICU 
X 
 
 
 
Discharge Disposition 
X 
 
 
 
Antibiotic Use 
X 
 
 
 
Clinical Follow-up Assessments 
 
 
 
 
Deep Surgical Site Infection 
 
X 
X 
X 


 
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Assessment 
Base-
line 
2 
Week
s 
3mo 
6mo 
Complications (type, severity, treatment) 
 
X 
X 
X 
Wound Healing 
 
X 
X 
X 
Antibiotic Use 
 
X 
X 
X 
Fracture Healing 
 
X 
X 
X 
Pain 
 
X 
X 
X 
Self Reported Assessments 
 
 
 
 
Re hospitalizations 
 
X 
X 
X 
Self reported pain 
 
 
 
X 
Brief Pain Inventory 
 
 
 
X 
Health Related Quality of Life (VR-12) 
 
 
 
X 
Short Musculoskeletal Function 
Assessment (SMFA) 
 
 
 
X 


 
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APPENDIX D: CONSENT TEMPLATE 
 
INFORMED CONSENT DOCUMENT 
 
Draft Participant Consent Form 
 
Study Title:  Local Antibiotic Therapy to Reduce Infection after Operative Treatment of Fractures at 
High Risk of Infection: A Multicenter Randomized Controlled Trial 
Principal Investigator: Robert V. O’Toole, MD, MS 
 
 
You are being asked to volunteer to be a part of a research study.  Please read this form carefully 
before you sign it. This consent form explains the research study and your part in the study.  If 
you decide not to participate in this study there will be no impact on your medical care.  You can 
choose not to take part and if you join, you may quit at any time.  Ask the study doctor or the 
study staff to explain any words or procedures that you do not clearly understand.  Ask as many 
questions as needed.  All of your questions should be answered to your satisfaction before you 
sign this form.  
 
 
1. WHAT IS THE PURPOSE OF THIS RESEARCH STUDY? 
 
This research is being done to help determine the best treatment for severe lower leg injures like 
yours. Some broken bone injuries can be more likely to get an infection. It is mostly due to the 
way they were injured. These injuries are: a break in the top of your tibia (larger bone in your 
lower leg), or a break in your pilon (break in the bottom part of your tibia (larger bone in your 
lower leg)). 
 
Surgical site infection in the orthopaedic surgery population is a big public health issue. 
Wound infections result in both longer length of hospital stay and total cost of care. 
This study will be using an antibiotic called Vancomycin. This antibiotic is usually given using 
an injection (intravenous (IV) format).  
 
Some research has been done with spine surgery. The research has shown that by using local 
antibiotics in the form of a powder sprinkled right in the site of surgery can  
have a smaller risk for infection later. In these studies there were no reports of problems for 
participants. Many orthopaedic surgeons are now using this antibiotic powder as part of their 


 
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standard clinical practice. We would like to see if this works the same with people who have 
surgery for a broken leg bone. 
 
 
This study is funded by the Department of Defense (DOD) and is being carried out in more than 
25 major trauma centers across the United States, including four Military Treatment Facilities 
that are taking care of service members who are injured in the line of duty.  
 
2. WHY AM I BEING ASKED TO PARTICIPATE? 
 
You are being asked to participate in this study because you are between the age of 18 and 80 
and you have a severe injury of the lower leg, or ankle. People like you who are being treated at 
major trauma centers from around the county are being asked to participate. You are one of over 
1000 patients we are asking to join this study. 
 
3. HOW LONG WILL THE STUDY LAST? 
 
Your participation in this study will last for 6 months following your injury.  
 
4. HOW DOES THE STUDY WORK? 
If you agree to participate in this study, we will fix your broken bone as we normally 
would. The only change to normal care would be to randomize (this is like the flip of a coin) you 
to one of two groups.  
 
Group 1 will receive antibiotic (Vancomycin) powder at your surgery site during your surgery in 
addition to the standard of care antibiotic treatment at your facility (care that would be no 
different than what you would receive if you were not in the study). If you are in Group 1 you 
will not be charged for the antibiotic powder.  
 
If you are in Group 2, you will get the standard of care antibiotic treatment at your facility (care 
that would be no different than what you would receive if you were not in the study).  
 
After your surgery, your care will be exactly the same as if you were not in the study.  You will 
be asked to come back to the clinic and follow up with us at 2 weeks, 3 months, and 6 months 
after your surgery. These visits coincide with times you would normally come back to see your 
physician for a check-up.  During these visits the following things will happen: 
 
• You will have a physical exam   


 
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• Because you are in the study, you will be asked additional questions by a member of the 
study team. These questions will typically take about 5 minutes of your time and will 
usually be asked while you are waiting to see your surgeon.  
• We will check to see if you have been re-hospitalized for your injury since your last 
follow-up visit. If you have, we will gather the details about the hospitalization from 
your medical record.  
• We will ask you if you have had any problems with your injured leg and if you have 
been told you have an infection by any of your doctors outside of this facility. 
• You will also be asked if you are taking any kind of medication for any kind of 
infection.  
In addition, at the 6 month study visit we would like to ask you some questions about pain, your 
health and general well being. These questions are widely used in research and have been found 
to be useful in finding out how you are doing after your injury. These include the Brief Pain 
Inventory (BPI), Short Form Musculoskeletal Assessment (SMFA), and the Veterans Rand 12 
item Health Survey (VR12). The questions should take you approximately 10 minutes to answer.  
 
 
5. WHAT ARE THE POTENTIAL RISKS OR DISCOMFORTS? 
 
There are standard risks with surgery. These will be explained to you along with your 
consent for surgery.  There are also standard risks associated with receiving any antibiotics. One 
risk is developing resistance to the antibiotic you will receive. There may also be risks of using 
Vancomycin in powder form that are not yet known. This use of Vancomycin has not been 
approved by the FDA, but some doctors use the drug in this manner outside the study. The FDA 
has permitted this use for this study.  
 
The risk of giving you antibiotic powder is increased for those of you who have an allergy to the 
drug Vancomycin. In addition, there is increased risk for those of you who are susceptible to 
local toxicity to the drug. If you have a known risk to antibiotics please talk with your treating 
surgeon.  
 
Any time information is collected for a study there is a small risk of breach of confidentiality. As 
described below, your research data will be identified by a unique study number rather than your 
name and all measures allowed by law to protect your confidentiality will be taken by the 
research staff. 
 
6. WHAT ARE THE POTENTIAL BENEFITS? 
 


 
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As a result of your participation in this study you will receive more focused clinical follow-up. 
At your 6 month visit you will be assessed for pain, health and general well-being and will 
undergo a musculoskeletal function assessment in addition to your standard clinical evaluation. 
In addition, you will be further evaluated using specific questions related to pain and your 
activity level (Brief Pain Inventory (BPI), Short Form Musculoskeletal Assessment (SMFA), and 
the Veterans Rand 12 item Health Survey (VR12).   
 
7. DO I GET ANY PAYMENT FOR BEING IN THE STUDY? 
 
You will receive $50 each for completing the 6 month visit.  This payment is in appreciation of 
your time and effort. 
 
8. ARE THERE ANY COSTS INVOLVED IN BEING IN THE STUDY? 
 
If you are randomized to receive the Vancomycin powder, it will be paid for by the study. There 
is no cost to you to participate in this study. 
 
9. WILL MY INFORMATION BE KEPT PRIVATE? 
 
The information we collect from you will be kept private to the best of our ability. Your name, 
birth date, medical record number and any other information that could identify you as an 
individual will be removed from all study forms. Instead, we will label your forms with a unique 
study number. The link between your name and your study number will be kept confidential to 
the greatest extent provided by law. The information collected for the study will be stored in a 
password protected, HIPAA verified computer database that only authorized members of our 
research team can use. When we report the results of the study, we will combine the information 
about you with similar information about hundreds of other people so your individual 
information will not be identifiable.  
 
All study records will be considered confidential, and your name will not be used in reports or 
publications.   
 
10. WILL YOU SHARE MY INFORMATION WITH OTHERS? 
 
We will use your information only for the purposes of this study. The data from the study may be 
published. However, you will not be identified by name. People designated from the institutions 


 
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where the study is being conducted will be allowed to inspect sections of your medical and 
research records related to the study. This includes people designated by The Johns Hopkins 
Bloomberg School of Public Health who are overseeing this study.  Everyone using study 
information will work to keep your personal information confidential. Your personal information 
will not be given out unless required by law. 
 
The Department of Defense is providing funding to sponsor this study. Federal or DoD 
representatives and your local IRB may have access to research records in their role to 
protect human subjects engaged in research.  
11. WHAT ARE MY ALTERNATIVES TO PARTICIPATION? 
 
Your alternative is to not take part in the study. If you choose not to take part, your healthcare 
will not be affected. 
 
12. WHAT HAPPENS IF I LEAVE THE STUDY EARLY? 
 
Your participation in this study is completely voluntary. You have the right to withdraw from the 
research study at any time without penalty. Your decision will not affect the medical care you 
receive. If you decide to stop participating, you should notify the study doctor or the research 
coordinator at your center.  
 
Your participation in this research study could be ended without your consent if we decide to end 
the study early. You may also be withdrawn from the study if your injury is not determined to be 
severe enough for inclusion.  
 
13. WHAT HAPPENS IF I AM INJURED OR BECOME ILL BECAUSE I TOOK PART 
IN THIS STUDY? 
 
If you are injured or become ill because of your participation in this study, you will receive 
emergency medical care if needed and you will receive assistance in getting other medical care 
as needed.  You or your insurance carrier will be billed for the cost of care, just as you would be 
billed for any other medical care.  If you have any costs that are not covered by insurance, they 
are your responsibility.   
 


 
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You do not give up any of your legal rights by signing this form. You can seek legal 
compensation for any injury that may occur to you during the study as a result of an error by a 
member of the research staff or others.  
 
14. WHO DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
 
• <<insert name>>, the study coordinator at your hospital has discussed this information 
with you and offered to answer any questions you may have.   If you have further 
questions or get sick or injured as a result of being in this study, you can contact << insert 
him/her>> at <<telephone number>>.  You may also call the Director of the Study at 
your hospital, <<insert name>>, at <<telephone number>>.   
 
• If you have further questions about your rights as a study participant you can call or 
contact your local IRB office or the Johns Hopkins Bloomberg School of Public Health 
IRB Office. The Johns Hopkins Bloomberg School of Public Health is serving as the 
overall coordinating center for this study that is being conducted in hospitals around the 
country. Contact the Johns Hopkins IRB if you feel you have not been treated fairly or if 
you have other concerns.  The IRB contact information is:   
 
• <<insert local IRB contact information here>> 
 
You will receive a copy of this signed consent form. 
 
 
 
What does your signature (or thumbprint/mark) on this consent form mean? 
 
Your signature (or thumbprint/mark) on this form means: 
 
• You have been informed about this study’s purpose, procedures, possible benefits and 
risks. 
• You have been given the chance to ask questions before you sign. 
• You have voluntarily agreed to be in this study.  
 
________________________              _____________________________   ________   
Print name of Adult Participant              Signature of Adult Participant           Date          Time                               


 
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Ask the participant to mark a “left thumb impression” in this box if the participant (or 
participant’s parent) is unable to provide a signature above.  
 
 
________________________        _____________________________       __________  
Print name of Person Obtaining     Signature of Person Obtaining Consent   Date             Time                              
Consent 
APPENDIX E: EVALUTION TO GIVE CONSENT 
 
EVALUATION TO GIVE CONSENT 
 
Procedure: Make a subjective judgment regarding item 1 below.  Ask questions 2 through 4. You 
may select the language to use in asking the questions in order to help the respondent 
understand them.  
 
 
1. 
Is the respondent alert and able to communicate with you? 
 
Yes ___ 
No ____   (if condition not likely to change, seek proxy 
consent)  
 
2. 
Ask the respondent to name at least one thing that s/he will be asked to do as part of the 
study. 
 
Describe________________________________________________________________
________________________________________________________________________ 
 
3. 
Ask the respondent to explain what s/he could do if s/he decided s/he did not want to 
participate in the study. 
 
Describe________________________________________________________________
________________________________________________________________________ 
 


 
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4. 
Ask the respondent to explain what s/he would do if s/he were experiencing distress or 
discomfort at any time during the study. 
 
Describe________________________________________________________________
________________________________________________________________________ 
 
I hereby certify that the above-named respondent is alert, able to communicate, and able to give 
acceptable answers to items 2, 3, and 4, above. 
 
____________________________________         ____________________________________ 
Research Coordinator                                                            Date 


 
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APPENDIX F: BROCHURE INSERT 
Be Part of the Local Antibiotic Powder (VANCO) Team! 
Help advance limb trauma care through research 
 
What is the Local Antibiotic Powder Study? 
Very bad breaks of the lower leg and ankle are difficult to treat and are associated with infection 
and other complications. The goal of VANCO is to determine whether a higher amount of using 
local antibiotics in a powder form during surgery can reduce your risk of infection.  
 
Why me? 
This VANCO study is funded by the Department of Defense (DOD) and is being carried out in 
more than 25 major trauma centers across the United States, including four military treatment 
centers that are taking care of service members who are injured in the line of duty.  
 
You are being asked to participate in this study because you have a badly broken bone in your 
lower leg or ankle that your surgeon has determined is bad enough to qualify for the study.   
People with injuries similar to yours who are being treated at major trauma centers from around 
the county are being asked to participate.   
 
How does the study work?  
We will observe the outcomes of your treatment and we will follow your recovery. 
After you sign this informed consent and agree to be part of the study, the following things will 
happen: 
• You will be randomized to either standard of care antibiotics or some additional local 
antibiotic (Vancomycin) powder placed in your surgical wound at the time of surgery to 
fix your broken bone.  
• Information will be collected about your injury and your surgery from your medical record 
and your surgeon and will be entered into a database by a member of the research team. 
• You will receive surgery to treat your injury. You and your surgeon will decide on the 
best course of treatment. 
 
After your surgery your care will be exactly the same as if you were not in the study.  You will 
be asked to come back to the clinic and follow up with us at 2 weeks, 3 months, and 6 months 
after your surgery. During these visits the following things will happen: 
• You will have a physical exam 
• An x-ray will be taken to see how your bone is healing 
• You will be asked about any treatment to your leg that you have had other than with your 
surgeon  
• You will be asked if any doctor other than your surgeon has told you that you have an 
infection in that leg 
• You will also be asked if you are taking any antibiotics for any infection.  


 
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We will take a look at your surgical site and ask you some general questions about your health.  
We hope you will consider taking part in the VANCO study.  It is a way to be part of a 
nationwide effort and to help advance limb trauma care for others in the future.  Please talk to 
your doctor about participating, or visit www.METRC.org to learn more.  
 


 
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APPENDIX G: INTERVIEWS 
 
[Will submit SF12, SMFA, BPI to IRB and will attach separately] 

SAP_001.pdf: 
1 
VANCO: 
Statistical Analysis Plan for Main Outcome Paper 
(Revision 2) 
NCT02227446
February 4, 2020 
Revision 2 Information: 
• Section 5, “nd” changed to “and”
• Section 8.2: “surgery during the index hospitalization” changed to
“definitive fixation surgery”
Revision 1 (9/7/18) Information: 
• Section 8.1: “The primary way in which the presence or absence of the
occurrence of clinical outcome events are ascertained is through study
follow-up visits. Presence/absence of events are also ascertained via
medical record reviews where there is documented orthopaedic con- 
tact.” changed to “The primary way in which clinical outcome events
are ascertained is through study follow-up visits. Presence/absence of
infection events are also ascertained via medical record reviews where
there is documented orthopaedic contact.”
• Section 8.3: “Key secondary outcomes include: (1) superficial surgical
site infection, (2) loss of limb/amputation, (3) fixation failure,  (4)
wound dehiscence, (5) wound seratoma/hematoma  and  (6)  surgical
site infection at other surgical site. If multiple events for a given
secondary outcome occur for an individual, only the timing of the first
event will be considered. Treatment effects will be analyzed using the
same approach described for the primary outcome.” changed to “Key
secondary outcomes include: (1) superficial surgical site infection, (2)
loss of limb/amputation, (3) fixation  failure,  (4)  wound  dehiscence
and (5) wound seratoma/hematoma. If multiple events for a given


2 
secondary outcome occur for an individual, only the first event will 
be considered. For superficial surgical site infection, treatment effects 
will be analyzed using the same approach described for the primary 
outcome. To the extent possible, treatments effects for other secondary 
outcomes will be analyzed using the window-based method.” 
• Section 8.4: “Treatment effects will be analyzed using the same ap- 
proach described for the primary outcome.” changed to “To the extent
possible, treatments effects for these outcomes will be analyzed using
the window-based method.”
The statistical analysis plan was finalized prior to database lock. Prior 
to database lock, the only analyses that were performed were (1) those 
masked to treatment group for purposes of DSMB reporting, (2) evaluation 
of background rates (to assess design assumptions) in August 2016, and 
(3) a formal DSMB interim analysis of the primary outcome conducted in
November 2016.
1 
CONSORT Diagram 
The CONSORT Diagram will report the following items in sequential order: 
(1) the number screened patients, (2) the number of patients not enrolled
and associated reasons, (3) the number of enrolled and randomized patients,
(4) number randomized to treatment group, number randomized to control
group, (5) within treatment group, the number of late ineligibles and late
refusals and whether they received treatment, (6) within treatment group,
number of cross-overs, (7) within treatment group, number included in sur- 
vival analysis- and window-based analyses with summary statistics related
to missing/censored data. Late ineligibles and late refusals will be removed
from all analyses. The outcomes, complications, adverse events of late inel- 
igibles and late refusals who received treatment will be reported.
2 
Follow-up Time 
Patients were expected to return for study follow-up visits at 2 weeks, 3 
months and 6 months. In addition, medical record reviews were conducted 
to determine whether there was documented orthopaedic contact beyond 
the last study follow-up visit. The end of follow up will be defined as the 
last study follow-up visit or the last orthopaedic contact if applicable, and 
follow-up time will be the duration between the last fixation procedure and 


3 
the end of follow up. A figure showing the distribution of follow-up time by 
treatment group will be produced. Differences between treatment groups 
will be evaluated by using Wilcoxon rank-sum test. Details of reasons for 
premature study discontinuation will be presented. 
3 
Pre-Injury Characteristics 
A table will report summary statistics for characteristics of participants prior 
to their injuries by treatment groups. Pre-injury characteristics include age, 
gender, education, body mass index, tobacco use, alcohol abuse, drug abuse, 
diabetes, poverty status1, previous injury to study leg, pre-injury infection 
and associated treatment and pre-injury VR-12 (general health, physical 
component score, mental component score). 
4 
Injury Characteristics 
A table will report summary statistics for injury characteristics by treatment 
groups. Injury characteristics include bone segment (tibia plateau/tibia 
pilon), fracture pattern per the AO/OTA classification (B/C), open frac- 
ture (yes/no), Tscherne classification (among closed fractures), Gustilo type 
(among open fractures), OTA Open Fracture Classification (including con- 
tamination, bone loss, muscle damage, skin damage, and arterial damage) 
and severity of injuries other than study injury (as measured by AIS). 
5 Pre-, Intra-, and Post- Operative Care Charac- 
teristics 
A table will report summary statistics for pre-, intra- and post-operative 
care characteristics by treatment groups. These characteristics will include 
pre-operative risk stratification (ASA, nasal swabs2), nutrition lab results, 
prophylactic antibiotic use (prior to skin incision), other antibiotic use (24 
hours prior to definitive fixation), number of stages prior to final fixation, 
days to definitive surgery (relative to injury), number and location of surgical 
incisions (stratified by fracture type), percutaneous insertion (yes/no), sur- 
gical site skin preparation, nasal application of Bactoban (yes/no), external 
1Derived variable based on self-reported income and household size; anticipated to have 
high rate of missingness. 
2MRSA swab is preoperative (prior to incision). MRSA positive is assumed to be risk 
for infection. 


4 
fixation removed during surgery (yes/no, if applicable), fraction of inspired 
oxygen (FiO2) during the surgery (yes/no), number of other procedures,
duration of surgery, use of tourniquet, operative environment, attending 
surgeon time in surgery (as percent of total surgery time), type of anesthe- 
sia, additional novel (per surgeon self report) techniques to reduce risk of 
infection (yes/no), use of a surgical drain (yes/no), incisional vac (negative 
pressure wound therapy, or NPWT) at surgical site (yes/no), planned time 
to allow range of motion, and peri-operative antibiotic treatment. 
6 
Adherence to Treatment Protocol and Protocol 
Deviations 
Patients randomized to the treatment arm should receive only one dose of 
local Vancomycin, consisting of 1 gram of powder. The study treatment 
should only be administered at the final stage of fixation if the procedure 
is done in multiple stages. Patients randomized to the control arm should 
not receive any local Vancomycin powder as part of their definitive fixation. 
Lack of adherence to the assigned treatment will be reported as protocol 
deviations, the details of which will be reported by treatment group. Among 
patients who received local Vancomycin powder, including those that crossed 
over from the control arm, the method of application and severe allergic 
reaction to local Vancomycin powder (yes/no) will be reported. 
7 
Serious Adverse Events and Complications Other 
than Outcomes 
A table will report a summary of deaths, life-threatening or disabling events, 
and complications other than outcomes, stratified by treatment group. 
8 
Outcome Analyses 
8.1 Ascertainment 
The primary way in which clinical outcome events are ascertained is through 
study follow-up visits. Presence/absence of infection events are also ascer- 
tained via medical record reviews where there is documented orthopaedic 
contact. 


5 
 
 
 
 
 
8.2 Primary Outcome 
The primary outcome is the presence of clinically significant deep infection 
(as determined by adjudicators applying CDC guidelines)3 by 6 months after 
the last definitive fixation surgery. There are two ways that the results will 
be reported: (1) time-to-event-based, and (2) window-based. 
The first method is based on survival analysis techniques.4 Specifically, 
Kaplan-Meier (KM) methods will be used to estimate, separately for each 
treatment group, the probability of a deep infection by 182 days. Addi- 
tionally, 95% confidence intervals for the difference and ratio of treatment- 
specific probabilities of deep infection by 182 days will be computed. Kaplan- 
Meier curves for both treatment groups will be produced. 
The second method is based on the creation of a 42-day (i.e. six week) 
window around day 182.5 A patient is said to have a deep infection if, had 
they been assessed within the window,  they would have been recorded to 
have experienced a deep infection prior to the assessment time. This binary 
outcome will be counted for patients who were observed to have an infection 
prior to day 140 AND all patients whose end of follow-up was after day 140. 
That is, the outcome will be unobserved for those whose end of follow-up is 
prior to day 140 AND did not experience a deep infection during follow-up. 
6 The treatment-specific probability of deep infection will be estimated by 
using the observed outcomes. 95% confidence intervals for the difference and 
ratio of treatment-specific probabilities of deep infection will be computed. 
A test of treatment difference will be evaluated using Fisher’s exact test. 
Sensitivity analyses will be conducted to evaluate the robustness of re- 
sults. Examples include altering the permissible follow up window width, 
using last study follow-up visit as the end of follow-up (rather than including 
last orthopaedic contact), and addressing informative missingness/censoring 
by adjusting for key baseline covariates predictive of infection (e.g., fracture 
type, ASA grade). 
For all deep infections, the ASEPSIS score will be summarized by treat- 
ment group. 
3Details of the adjudication process and its findings will be reported. 
4This method was used for the interim analysis, when ascertainment was not complete. 
5This is consistent with what was proposed in the protocol paper. 
6It was assumed that the fraction of patients with unobserved data would be less than 
5%. During the blinded ascertainment process, it became clear that the fraction would be 
larger than 5%. As a result, the first method may make more efficient use of the observed 
data. 


6 
 
 
 
 
 
8.3 Secondary Outcomes 
Key secondary outcomes include: (1) superficial surgical site infection, (2) 
loss of limb/amputation, (3) fixation failure, (4) wound dehiscence and (5) 
wound seratoma/hematoma. If multiple events for a given secondary out- 
come occur for an individual, only the first event will be considered. For 
superficial surgical site infection, treatment effects will be analyzed using the 
same approach described for the primary outcome. To the extent possible, 
treatments effects for other secondary outcomes will be analyzed using the 
window-based method. 
 
8.4 Tertiary Outcomes 
Key tertiary outcomes include: (1) nonunion, (2) malunion, (3) flap failure, 
(4) peri-implant fracture, (5) reaction to hardware. If multiple events for 
a given tertiary outcome occur for an individual, only the first event will 
be considered. To the extent possible, treatments effects for these outcomes 
will be analyzed using the window-based method. 
 
9 
Subgroup Analyses 
Two key subgroup analyses will be conducted with regards to the primary 
outcome: plateau/pilon and open/closed. An interaction test will be per- 
formed to evaluate if there is statistical evidence of differential subgroup 
effects within subgroup categories. Treatment effects within subgroups will 
be reported using the same approach described for the primary outcome. 


7 
 
Daniel 
Scharfstein 
Digitally signed by Daniel 
Scharfstein 
Date: 2020.02.04 20:22:06 
-05'00' 
 
Prepared by: 
Daniel O. Scharfstein (ScD), Principal Biostatistician 
Yanjie Huang (BM, ScM), Data Analyst 
 
Approved by: 
Robert V. O’Toole (MD, MSME), Principal Investigator 
Renan C. Castillo (PhD), MCC Investigator 
Anthony R. Carlini (MS), Project Director