PREPARE: A Pragmatic Randomized Trial Evaluating Pre-operative Alcohol Skin Solutions in FRactured Extremites
Phase: PHASE4
Conditions: Surgical Site Infection, Unplanned Fracture-Related Reoperation, Open Appendicular Fracture, Closed Lower Extremity Fracture, Pelvic Fracture
Sponsor: University of Maryland, Baltimore

 
 
PREP-IT 
A Program of Randomized trials to Evaluate Pre-operative 
antiseptic skin solutions In orthopaedic Trauma 
 
 
 
PREPARE: A Pragmatic Randomized trial Evaluating Pre-operative 
Alcohol skin solutions in FRactured Extremities 
 
 
 
PREPARE PROTOCOL 
 
 
Version: 2.2 
 
Date: 12-January-2021 
 
This study is funded by the Patient-Centered Outcomes Research Institute (PCORI) 
(PCS-1609-36512). 
 
The PREPARE trial is part of the PREP-IT research program. The protocol is the 
confidential intellectual property of the Principal Investigators and PREP-IT Steering 
Committee, and the protocol cannot be used in any form without the expressed written 
permission of the Principal Investigators. 
 
Reviewed and Approved by: 
  
 
Dr. Gerard Slobogean  
(Principal Investigator)  
Signature: 
Date: 12-Jan-2021 
 
Dr. Sheila Sprague 
(Principal Investigator) 
Signature: 
Date: 12-Jan-2021 
 
Dr. Mohit Bhandari  
(Principal Investigator) 
Signature: 
 
Date: 12-Jan-2021 
 
 
 
 
Trial Registration: clinicaltrials.gov, NCT03523962. Registered May 14, 2018,
https://clinicaltrials.gov/ct2/show/NCT03523962 

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TABLE OF CONTENTS  
LIST OF ABBREVIATIONS .......................................................................................... 4 
STUDY SUMMARY ......................................................................................................... 5 
1.0 INTRODUCTION ....................................................................................................... 8 
1.1 Extremity Fractures and Surgical Site Infections ..................................................... 8 
1.2 Prevention of Infection ............................................................................................. 8 
1.3 Rationale for Pre-Operative Antiseptic Skin Solution Prophylaxis .......................... 8 
1.4 Extrapolating Evidence from Other Surgical Disciplines to Fracture Surgery is 
Problematic ................................................................................................................... 10 
1.5 Why Iodophor Skin Preparations May Reduce Operative Extremity Fracture SSI 11 
1.6 Why Iodophor Skin Preparations May Reduce Extremity Fracture Reoperations . 11 
1.7 Lack of Surgeon Consensus .................................................................................... 12 
2.0 STUDY OBJECTIVES AND HYPOTHESES ....................................................... 12 
2.1 Study Objectives and Hypotheses ........................................................................... 12 
2.2 Open and Closed Fracture Study Populations ........................................................ 13 
2.3 Subgroup Objectives ............................................................................................... 13 
2.3.1 Open Fracture Subgroups ................................................................................ 13 
2.3.2 Closed Fracture Subgroups .............................................................................. 13 
2.3.3 Subgroup Hypotheses ...................................................................................... 13 
3.0 TRIAL DESIGN ........................................................................................................ 14 
3.1 Summary ................................................................................................................. 14 
3.2 Pragmatic-Explanatory Continuum ........................................................................ 15 
4.0 METHODS ................................................................................................................ 16 
4.1 Study Setting, Cluster Eligibility, and Selection of Clusters .................................. 16 
4.2 Eligibility Criteria ................................................................................................... 17 
4.2.1 Open Fracture Population Eligibility Criteria .................................................. 17 
4.2.2 Closed Fracture Population Eligibility Criteria ............................................... 18 
4.2.3 Additional Eligibility Considerations .............................................................. 18 
4.3 Recruitment Strategy .............................................................................................. 19 
4.3.1 Patient Screening & Consent ........................................................................... 19 
4.4 Managing Patient Volume ...................................................................................... 20 
4.4.1 Enrollment of Patients from Only One Fracture Cohort .................................. 20 
4.4.2 Enrollment Sampling Plan ............................................................................... 21 
4.4 Randomization Methods ......................................................................................... 21 
4.5 Blinding ................................................................................................................... 21 
4.6 Description of the Interventions .............................................................................. 22 
4.6.1 Initial Run-In Phase ......................................................................................... 22 
4.6.2 First Intervention Phase ................................................................................... 22 
4.6.3 Second Intervention Phase ............................................................................... 23 
4.6.4 Special Considerations for Ongoing Treatment Crossovers ............................ 23 
4.6.5 Evaluation of Site Performance and Removal of Clinical Sites ...................... 23 
4.6.6 Application of Pre-Operative Antiseptic Skin Solutions ................................. 23 
4.6.7 Patients with Multiple Planned Surgeries ........................................................ 24 
4.6.8 Iodophor Antiseptic Solution ........................................................................... 24 

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4.6.9 CHG Antiseptic Solution ................................................................................. 24 
4.7 Perioperative Co-Interventions ............................................................................... 24 
4.8 Outcome Measures .................................................................................................. 25 
4.8.1 Primary Outcome ............................................................................................. 25 
4.8.2 Secondary Outcome ......................................................................................... 27 
4.8.4 Data Collection and Participant Follow-up ...................................................... 28 
5.0 STATISTICAL PLAN .............................................................................................. 29 
5.1 Sample Size Determination ..................................................................................... 29 
5.2 Statistical Methods .................................................................................................. 31 
5.2.1 Analysis Plan Overview ................................................................................... 31 
5.2.2 Analysis of the Study Outcomes ...................................................................... 32 
5.2.3 Subgroup Analyses .......................................................................................... 32 
5.2.4 Sensitivity Analyses ......................................................................................... 33 
5.2.5 Interim Analysis ............................................................................................... 35 
6.0 DATA MANAGEMENT .......................................................................................... 36 
6.1 Case Report Forms and Data Transmission ............................................................ 36 
6.2 Data Integrity .......................................................................................................... 36 
7.0 ETHICS AND DISSEMINATION .......................................................................... 36 
7.1 Research Ethics Approval ....................................................................................... 36 
7.2 Consent ................................................................................................................... 36 
7.3 Confidentiality ........................................................................................................ 38 
7.4 Protocol Amendments ............................................................................................. 38 
7.5 Adverse Event Reporting and Definitions .............................................................. 38 
7.5.1 Serious Adverse Event (SAE) .......................................................................... 38 
7.5.2 Unanticipated Problems Resulting in Risk to Participant or Others ................ 39 
7.5.3 Serious Unexpected Adverse Drug Reactions ................................................. 39 
7.5.4 Adverse Event Reporting ................................................................................. 39 
7.5.5 Clinical Site Reporting – IRB and REB .......................................................... 40 
7.5.6 Data and Safety Monitoring Committee .......................................................... 40 
7.6 Dissemination Policy .............................................................................................. 40 
8.0 SUB-STUDY: PATIENT EXPERIENCES IN THE AQUEOUS-PREP AND 
PREPARE TRIALS ........................................................................................................ 40 
8.1 Introduction ............................................................................................................. 40 
8.2 Rationale and Objectives ........................................................................................ 41 
8.3 Sub-Study Design ................................................................................................... 41 
8.4 Survey Participants and Distribution ...................................................................... 41 
8.5 Data Entry ............................................................................................................... 42 
8.6 Sample Size ............................................................................................................. 42 
8.7 Data Analysis .......................................................................................................... 42 
8.8 Anticipated Implications of Results ........................................................................ 42 
9.0 SUB-STUDY: THE IMPACT OF HETEROTOPIC OSSIFICATION 
PROPHYLAXIS AFTER SURGICAL FIXATION OF ACETABULAR 
FRACTURES: NATIONAL TREATMENT PATTERNS AND RELATED 
OUTCOMES ................................................................................................................... 42 

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9.1 Introduction ............................................................................................................. 42 
9.2 Rationale and Objectives ........................................................................................ 43 
9.3 Sub-Study Design ................................................................................................... 43 
9.4 Data Entry ............................................................................................................... 43 
9.5 Sample Size ............................................................................................................. 43 
9.6 Data Analysis .......................................................................................................... 43 
9.7 Anticipated Implications of Results ........................................................................ 44 
10.0 SUB-STUDY: MEASUREMENT OF TROPONIN FOLLOWING FRACTURE 
REPAIR SURGERY ....................................................................................................... 44 
10.1 Introduction ........................................................................................................... 44 
10.2 Rationale and Objectives ...................................................................................... 45 
10.3 Sub-Study Design ................................................................................................. 45 
10.4 Data Entry ............................................................................................................. 45 
10.4 Sample Size ........................................................................................................... 45 
10.5 Data Analysis ........................................................................................................ 45 
10.6 Anticipated Implications of the Results ................................................................ 46 
10.0 REFERENCES ........................................................................................................ 46 
 
 
 
 
LIST OF ABBREVIATIONS  
Abbreviation 
Explanation 
 
CDC 
CEO 
CHG 
CI 
CRF 
EDC 
FDA 
FLOW 
FRI 
ITT 
IRB 
PREPARE 
 
REB 
SAE 
SSI 
HO 
MINS 
Centers for Disease Control and Prevention 
Center for Evidence-Based Orthopaedics 
Chlorhexidine gluconate 
Confidence interval 
Case report form 
Electronic data capture 
Food and Drug Administration 
Fluid Lavage of Open Wounds trial 
Fracture-Related Infection 
Intention-to-treat 
Institutional Review Board 
A Pragmatic Randomized trial Evaluating Pre-operative Alcohol 
skin solutions in FRactured Extremities 
Research Ethics Board 
Serious adverse event 
Surgical site infection 
Heterotopic ossification 
Myocardial injury after noncardiac surgery 

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STUDY SUMMARY   
 
Methodology 
Cluster randomized crossover design. 
Coordinating Center 
This study will be centrally coordinated by the Methods Center at the 
Center for Evidence-Based Orthopaedics (CEO), McMaster 
University, Hamilton, Ontario and by the Administrative Center 
within the Department of Orthopaedics at the University of 
Maryland, R Adams Cowley Shock Trauma Center, Baltimore, 
Maryland.  
Clinical Sites 
At least 18 clinical sites in North America. Additional clinical sites 
will be included or removed as needed. 
Background 
The prevention of infection is an important goal influencing peri-
operative care of extremity fracture patients.  Standard practice in the 
operative management of extremity fractures includes sterile 
technique and pre-operative skin preparation with an antiseptic 
solution. The available solutions kill bacteria and decrease the 
quantity of native skin flora, thereby decreasing surgical site infection 
(SSI). While there is extensive guidance on specific procedures for 
prophylactic antibiotic use and standards for sterile technique, the 
evidence regarding the choice of antiseptic skin preparation solution 
is very limited for extremity fracture surgery.  
Objectives 
The overarching objective of this trial is to compare the effectiveness 
of iodine povacrylex (0.7% free iodine) in 74% isopropyl alcohol 
versus 2% chlorhexidine gluconate (CHG) in 70% isopropyl alcohol 
for the management of extremity fractures that require surgical 
treatment. The primary outcome for comparison is surgical site 
infection (SSI), and the secondary outcome is unplanned fracture-
related reoperation.  
Open and Closed 
Fractures Populations 
Open fracture patients and closed fracture patients represent two 
distinct populations within extremity fracture surgery.  Open and 
closed fracture participants will be recruited separately to 
independently compare the effectiveness of the study solutions in 
each population.  Therefore, our effectiveness comparisons will be 
performed separately within the open fracture and closed fracture 
populations. 
Subgroup Objectives 
The PREPARE trial will also explore the possibility of differential 
treatment effects of the pre-operative antiseptic skin solutions among 
clinically important subgroups. The open fracture subgroups will be 
defined by i) the severity of open fracture (Gustilo-Anderson type I 
or II versus III);1 ii) upper extremity versus lower extremity open 
fractures; iii) severity of wound contamination; and, iv) presence or 
absence of comorbidities that affect wound healing.  The closed 
fracture subgroups will be defined by: i) severity of soft tissue injury 

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(higher Tscherne injuries) and ii) presence or absence of 
comorbidities that affect wound healing. 
Diagnosis and Main 
Inclusion Criteria 
All patients 18 years of age or older who present to a recruiting 
hospital for treatment of an open fracture(s) of the appendicular 
skeleton will be screened for participation within 3 weeks of their 
fracture.  All patients 18 years of age or older who present to a 
recruiting hospital for surgical treatment of a closed lower extremity 
or pelvic fracture(s) will be screened for participation within 6 weeks 
of their fracture.  Eligible patients must have an open fracture of the 
appendicular skeleton or have a closed lower extremity or pelvic 
fracture, and their fractures must be definitively managed with a 
surgical implant (e.g., internal fixation, external fixation (open 
fractures and in closed fractures that require a surgical incision), joint 
prosthesis, etc.).  
Treatment Groups  
The PREPARE trial will compare the most common alcohol-based 
pre-operative antiseptic skin solutions used during extremity fracture 
surgery. The iodine-based treatment intervention is an antiseptic 
solution comprised of iodine povacrylex (0.7% free iodine) in 74% 
isopropyl alcohol. 3M™ DuraPrep™ [3M Health Care, St Paul, MN], 
will be the commercial product used. The CHG intervention is an 
antiseptic solution comprised of 2% CHG in 70% isopropyl alcohol.  
ChloraPrep® [CareFusion Inc., Leawood, KS, USA] will be the 
commercial product used. 
Randomization 
Treatment allocation will be determined using a cluster-randomized 
crossover trial design.  The open and closed fracture populations will 
be treated with the same allocated solution at all times during the trial.  
The order of treatment allocation for each orthopaedic practice will 
be randomly assigned using a computer-generated randomization 
table. Each site will start with the initially allocated study solution 
and eventually crossover to the other solution for their second 
recruitment period. This process of alternating treatments will repeat 
approximately every 2 months as dictated by the initial 
randomization.  
Study Outcomes 
The primary outcome is SSI, guided by the Centers for Disease 
Control and Prevention’s (CDC) National Healthcare Safety Network 
reporting criteria, which includes superficial incisional SSI within 30 
days and deep incisional or organ/space SSI within 90 days of 
definitive fracture management surgery. The secondary outcome is 
the occurrence of an unplanned fracture-related reoperation within 12 
months of the fracture.   Alternative definitions of SSI, including the 
confirmatory criteria for Fracture-Related Infection (FRI) and the 
CDC criteria within 1 year of injury will be used for sensitivity 
analyses of the primary comparison.  All study outcomes will be 
adjudicated by a blinded committee using clinical notes and 
radiographs.   

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Follow-Up  
Study participants will be followed at 6 weeks, 3 months, 6 months, 
9 months, and 12 months from their fracture.  
Sample Size 
A minimum of 1,540 participants with open fractures and a minimum 
of 6,280 participants with closed lower extremity or pelvic fractures 
will be included in PREPARE.  
Significance 
SSIs are often devastating complications for fracture patients because 
of the resultant reoperations, adverse events from antibiotic courses, 
and fracture healing difficulties.  Given the substantial impact of 
extremity fractures, maximizing the effectiveness of current 
prophylactic procedures is essential. The PREPARE trial will provide 
necessary evidence to guide the prevention of SSIs in fracture care, 
and the trial is poised to have a significant impact on the care and 
outcomes of extremity fracture patients.  

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1.0 INTRODUCTION 
 
1.1 Extremity Fractures and Surgical Site Infections 
More than one million Americans suffer an extremity fracture (broken bone in the arm, leg, or 
pelvis) that requires surgery each year.2,3 Approximately 5% (or 50,000) of surgical fracture 
patients develop a surgical site infection (SSI),4,5 which is twice the rate among most surgical 
patients and nearly five times the rate among patients undergoing elective orthopaedic surgeries 
(e.g., joint replacement).6  Patients who develop a SSI after their fracture fixation surgery 
experience a long and difficult treatment pathway. Researchers have identified that when a fracture 
patient experiences a SSI, they typically undergo at least two additional surgeries to control the 
infection, spend a median of 14 additional days in the hospital, and have significantly lower health 
related quality of life (HRQL).7 Similarly, results from the recently completed Fluid Lavage of 
Open Wounds (FLOW) trial confirmed that patients who had a SSI, or another complication, that 
required an additional surgery reported significantly lower physical and mental HRQL in the 12 
months following their fracture compared to patients who did not experience a SSI.8 In the most 
severe cases, when a SSI cannot be controlled, a limb amputation becomes necessary.  
 
Open fractures, closed lower extremity fractures, and pelvic fractures represent some of the most 
severe musculoskeletal injuries.9 Due to their high-energy mechanisms, these fractures are often 
accompanied by soft-tissue injuries that contribute to unacceptably poor outcomes. The FLOW 
trial of 2,447 open fracture patients reported a 13.2% incidence of open fracture-related 
reoperations;4 Closed fractures of the lower extremity are also at high risk of complications, 
particularly when compared to closed upper extremity fractures. For example, the rate of SSI in 
closed tibial plateau and plafond fractures range from 5.6 – 11.9%,10–14 although some cohort 
studies have reported infection rates as high as 25.0%.15 This is contrast with SSI rates of <5% for 
common upper extremity fractures like humeral shaft, forearm, or distal radius fractures.16,17  This 
is further illustrated in a series of 214 deep orthopaedic fracture infections, in which 58% occurred 
in the tibia and ankle, and only 10% occurred anywhere in the upper extremity.18  Finally, pelvic 
fractures are associated with some of the most challenging SSIs to treat among closed fractures 
because of their propensity to gram negative organisms and limitations in reconstruction options 
post-infection. Ultimately, infectious complications in these fracture populations lead to prolonged 
morbidity, loss of function, and potential limb loss.1  
 
1.2 Prevention of Infection 
The prevention of infection is the single most important goal influencing peri-operative care of 
patients with fractures that require surgical management. Standard practice in the management of 
extremity fractures includes sterile technique and pre-operative skin cleaning with an antiseptic 
solution. The available solutions kill bacteria and decrease the quantity of native skin flora, thereby 
decreasing SSI.19–22 While there is extensive guidance on specific procedures for prophylactic 
antibiotic use and standards for sterile technique, the evidence regarding the choice of antiseptic 
skin preparation solution is very limited for extremity fracture surgery.  
 
1.3 Rationale for Pre-Operative Antiseptic Skin Solution Prophylaxis 
The most common skin preparation solutions include either an iodophor or chlorhexidine-based 
active ingredient and are delivered in an alcohol or aqueous-based solution. Iodophors achieve 
effective antisepsis by penetrating the cell wall of microorganisms and disrupting critical protein 
and nucleic acid structures.23 Iodophors are effective against most bacteria, but also may have 
broader-spectrum coverage of mycobacteria, viruses, and some spores compared to chlorhexidine 

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gluconate (CHG).23 CHG similarly achieves antimicrobial effects by penetrating the cell wall of 
microorganisms. This antimicrobial action allows CHG to be effective against most bacteria.23 
 
The evidence guiding pre-operative antiseptic skin solution choice in fracture surgery is largely 
extrapolated from other surgical disciplines. In a randomized controlled trial involving 849 patients 
undergoing clean-contaminated abdominal, gynecologic, or urologic surgery, the use of 2% CHG 
in 70% isopropyl alcohol was compared to aqueous 10% povidone-iodine. The overall rate of 30-
day SSI was significantly lower in the CHG in alcohol group compared to the povidone-iodine 
group (9.5% vs. 16.1%; P=0.004; relative risk, 0.59; 95% confidence interval (CI): 0.41–0.85). 
While this study demonstrated superior efficacy of CHG in alcohol compared to povidone-iodine, 
comparing an alcohol based solution to an aqueous solution creates uncertainty about whether the 
result observed occurred from the superiority of CHG over iodine, isopropyl alcohol over water, 
or a synergistic combination of CHG in alcohol.19  In an effort to overcome the controversies 
associated with comparing CHG and iodine in different solutions, a more recent randomized 
controlled trial of 1,147 caesarean section patients allocated patients to 2% CHG in 70% isopropyl 
alcohol versus 8.3% povidone-iodine in 72.5% isopropyl alcohol. Similar to the previous 
randomized controlled trial, CHG proved more efficacious for reducing 30-day SSI (4.0% in the 
CHG in alcohol group and 7.3% in the iodine in alcohol group; relative risk, 0.55; 95% CI: 0.34–
0.90; P=0.02).20   
 
While the evidence from the above two randomized controlled trials demonstrates decreased SSI 
from CHG solutions in clean-contaminated abdominal and genito-urinary surgery, a larger non-
randomized trial reported opposite effectiveness results. Swenson et al., completed a larger 3,209 
patient pragmatic sequential implementation study, in which the use of the preoperative skin 
antiseptic solution was changed after six-month periods.21 In this study, there were three treatment 
periods, each with approximately 1,000 general surgery patients undergoing elective and emergent 
cases. In the first period, patients received 7.5% povidone-iodine scrub, 70% isopropyl alcohol 
scrub, and 10% povidone-iodine skin paint. The second group received 2% CHG in 70% isopropyl 
alcohol (CHG group), and the third group received 0.7% iodine povacrylex in 74% isopropyl 
alcohol. Adjusted comparisons were performed using the intention-to-treat (ITT) principle and an 
as-treated analysis. Lower SSI rates were seen in the povidone-iodine skin paint group (4.8%) and 
the iodine povacrylex in isopropyl alcohol group (4.8%), compared with the SSI rates in the 2% 
CHG in 70% isopropyl alcohol group (8.2%) (P< 0.05; povidone-iodine skin paint odds ratio: 0.56, 
95% CI: 0.40–0.79).21 While the results of the Swenson study contradict those of the smaller 
randomized controlled trials, this large pragmatic study further highlights that the choice of 
antiseptic skin solution affects SSIs, and data to select the best solution remain conflicting. 
 
Considering the conflicting data, the most recent Cochrane systematic review comparing the 
efficacy of pre-operative antiseptic skin solutions for clean surgery concluded, “investment in at 
least one large trial (in terms of participants) is warranted to add definitive and hopefully 
conclusive data to the current evidence base. Ideally any future trial would evaluate the iodine-
containing and CHG-containing solutions relevant to current practice…”24 The Cochrane 
recommendation is a direct response to the limitations of the current available literature comparing 
antiseptic skin solutions. For orthopaedic fracture surgery, the impact of the treatment uncertainty 
is further magnified when considering the higher rates of SSIs among open fracture patients and 
patients with closed lower extremity and pelvic fractures. 
 

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1.4 Extrapolating Evidence from Other Surgical Disciplines to Fracture Surgery is 
Problematic 
With regards to orthopaedic patients, the inconsistent results leave the optimal antiseptic solution 
in doubt; in addition, results may differ across surgical settings. The risk of SSI is substantially 
greater in certain fracture populations (open fractures, closed lower extremity fractures, and pelvic 
fractures) due to the soft tissue trauma, wound contamination in open fractures, the increased risk 
of local vascular disruption, and the required surgery to fix the broken bones. Furthermore, the 
emergent nature of fracture surgery means that patients are unable to undergo other prophylactic 
skin care, such as CHG bathing, which is rendered to elective cases to reduce SSI.  Additionally, 
the timing of prophylactic antibiotics may also fall beyond the recommended windows due to 
delays in getting to hospital; therefore, local antisepsis may become even more critical.  
 
Most important, the soft tissue injury associated with a fracture is a critical difference from elective 
abdominal or gynecologic surgery. Other differences include wound contamination in open 
fractures, the use of a tourniquet that decreases the blood flow to the limb (potentially increasing 
the risk of infection), and the additional risk of implanting metal fixation that can harbor bacteria. 
Swenson et al., directly acknowledged that the studies performed in general surgery patients may 
not apply to other specialties, particularly orthopaedic surgery.21 Even if one wanted to directly 
apply the conflicting results outlined above to the care of fractures, there are critical limitations in 
the sparse general surgery and obstetrical literature available.  
 
The most significant limitation in the existing literature is the use of a 30-day endpoint for SSI in 
all three studies described above.19–21 While this may be acceptable for identifying most SSIs that 
involve only the skin (superficial SSI), infections that occur deep to the muscle and around the 
bone (deep SSI and organ/space SSI) often present beyond 30-days post-injury and have 
significantly more morbidity and mortality than superficial SSIs. This is a major limitation to the 
external validity of the previous studies’ ability to guide fracture fixation practice. In the FLOW 
open fracture trial, nearly half the infection-related complications were identified between 30 and 
90 days from injury.4 Similarly, a large case series of patients who developed deep infections 
following fracture fixation found that post-operative infections occurred at an average of 77 days 
after surgery (range, 3 days to 51 weeks).18  While infections occurred earlier in patients with 
closed fractures, a substantial proportion occurred beyond 90 days (Figure 1).18   Not only does 
the existing literature not extend follow-up during this period, it is plausible that the treatment 
effects of the antiseptic solutions behave differently for preventing deep or organ/space infections 
that often present between 30 and 90 days post-surgery. The need for longer follow-up is supported 
by a mandatory 90-day surveillance period for deep and organ/space SSIs according to the Centers 
for Disease Control and Prevention (CDC).25 Therefore, the lack of directly applicable evidence, 
an overall paucity of good clinical evidence, and the inadequate duration of outcome follow-up 
mandate the need for a large, rigorous clinical trial in surgical preparation solutions in fracture 
care. 
 

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Figure 1: Time from Fracture Management Surgery Until SSI in Open and Closed Fractures 
 
1.5 Why Iodophor Skin Preparations May Reduce Operative Extremity Fracture SSI 
The only surgical skin preparation effectiveness data available for extremity fracture surgery come 
from the FLOW trial.4 Secondary multivariable analyses of 2,447 patients with open fractures 
found that when compared to CHG solutions, iodophor-based skin antiseptic preparation solutions 
could be protective against complications (Adjusted Hazard Ratio 0.88, 95% CI: 0.69–1.12).4 
However, the wide CI suggests iodophor solutions may reduce the odds of infection by as much 
as 31% or increase it by as much as 12%, leaving its superiority as a fracture care skin preparation 
solution unresolved.4 
 
There are several chemical properties to suggest iodine povacrylex may be more effective than 
CHG at preventing extremity fracture SSI.23 Firstly, iodine has a potentially broader spectrum of 
antimicrobial activity.23 Secondly, many open fracture patients require repeat surgical 
debridement, and therefore, these patients will receive multiple exposures to the pre-operative 
antiseptic solution. Extended use of iodophors has not been associated with the selection of 
resistant bacterial strains, whereas bacterial resistance to CHG has been documented.23,26,27 While 
the methods for detecting CHG resistance are challenging and its clinical significance remains 
uncertain, these early observations heighten interest in establishing the comparative effectiveness 
of iodophors versus CHG.  Finally, iodine povacrylex dries to form a water-insoluble polymer-
based film that increases its resistance to being washed away by saline and bodily fluids.21 This 
increased tissue adherence may contribute to increased antisepsis longevity compared to CHG 
solutions. 
 
1.6 Why Iodophor Skin Preparations May Reduce Extremity Fracture Reoperations 
While the primary rationale for using antiseptic skin preparation solutions is to reduce the risk of 
SSI, many fracture healing complications are associated with indolent infections. These low-grade 
infections typically do not exhibit clinical signs consistent with SSI. Instead, they present several 
months post-fracture fixation and are only detected from deep tissue samples collected during 
secondary surgeries to treat fractures that fail to heal (nonunion). Previous fracture nonunion 

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studies have identified an infectious etiology in 31–38% of cases.28,29 Similarly, results from the 
FLOW trial suggest that 58% of the reoperation events were caused by fracture nonunion or a 
hardware failure related to an infection, wound-healing problem, or bone-healing problem (n= 
188/323). This is consistent with the data presented in Figure 1, confirming a high proportion of 
fracture infections requiring surgery occurred beyond the 90-day surveillance period for SSI.18 
Therefore, given the rationale that iodophors may be more effective in preventing SSI, it is 
clinically plausible that its use may also reduce unplanned fracture-related reoperations. 
 
1.7 Lack of Surgeon Consensus 
The FLOW trial demonstrated a clear divide among orthopaedic surgeons regarding their choice 
to use the two most common antiseptic solutions during open fracture fixation surgery.4 Iodophor 
solutions were used in 54% of the surgeries performed, while 41% were performed using CHG 
solutions. The remaining surgeons either used both iodophor and CHG (4%), or alcohol with no 
iodophor or CHG (1%).4 Building upon the lack of consensus among orthopaedic surgeons 
participating in the FLOW trial, our research team conducted an internet-based survey (n = 210) 
and several interviews with orthopaedic surgeons to understand the reasons for the lack of 
consensus in the use of surgical preparation solutions. Similar to the observations of the FLOW 
trial, there was nearly an equal split between the use of iodophor and CHG solutions in open and 
closed fracture surgery. More insight was gained in interviews with the surgeons. Three main 
drivers for surgeon decision-making were identified: 1) they continued to use the antiseptic 
solution shown to them during their surgical training, 2) they used the solution recommended by 
their hospital, or 3) they felt the tissue toxicity was less with their chosen solution. No surgeon 
could cite a clinical study that helped guide their decision, despite all surgeons indicating they 
believed the antiseptic solution was important for reducing their patient’s risk of SSI. Limited 
consensus among surgeons reflects a lack of compelling evidence on the optimal approaches to 
surgical skin preparation, further vindicating the need for a large definitive trial. 
 
The PREPARE Trial, A Pragmatic Randomized trial Evaluating Pre-operative Alcohol skin 
solutions in FRactured Extremities, will address these gaps in the literature. 
 
2.0 STUDY OBJECTIVES AND HYPOTHESES 
 
2.1 Study Objectives and Hypotheses 
The overarching objective of this trial is to compare the effectiveness of iodine povacrylex (0.7% 
free iodine) in 74% isopropyl alcohol versus 2% CHG in 70% isopropyl alcohol for the 
management of extremity fractures that require surgical treatment. Open and closed fracture 
participants will be recruited separately to compare the independent effectiveness of the study 
solutions in each population. SSI will be the primary outcome for comparing effectiveness 
(primary objective), and unplanned fracture-related reoperation will be the secondary outcome 
for comparison (secondary objective). While previous randomized controlled trials in general 
surgery and gynecology demonstrated superior efficacy of CHG in alcohol solutions to reduce 
SSIs,19,20 results from larger populations of general surgery patients and the recently completed 
FLOW trial4 suggest iodophor-based solutions could be more effective than CHG in fracture 
patients. Therefore, we hypothesize that iodine-povacrylex is a more effective pre-operative 
antiseptic skin solution than CHG to reduce 90-day SSIs and unplanned fracture-related 
reoperations within one year of injury. 
 

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2.2 Open and Closed Fracture Study Populations 
Open fracture patients and closed fracture patients represent two distinct populations within 
extremity fracture surgery.  Open fractures are associated with wound complications that are 
approximately four times greater than closed fractures.4,5 The increased baseline risk, differing 
fracture treatment principles, and the distinct difference of having deep tissue exposed to micro-
organisms at the time of injury provides a biologic rationale for maintaining separate open and 
closed fracture populations.  This rationale is further strengthened by data collected from our 
surgeon survey that suggests many surgeons use different antiseptic skin prophylaxis procedures 
for open and closed fracture surgeries.  Therefore, definitively comparing the effectiveness of the 
study solutions in each fracture population addresses distinctly different treatment decisions for 
surgeons.  Similarly, if a difference in the effectiveness between the two study solutions were 
detected in only one of the fracture populations this would be an independently important clinical 
finding that would have an immediate effect on clinical practice.  
 
2.3 Subgroup Objectives 
The PREPARE trial will also explore the possibility of differential treatment effects of the pre-
operative antiseptic skin solutions among clinically important subgroups within each independent 
fracture population.   
 
2.3.1 Open Fracture Subgroups 
The open fracture subgroups will be defined by i) the severity of open fracture (Gustilo-Anderson 
type I or II versus III);1 ii) upper extremity versus lower extremity open fractures; iii) severity of 
wound contamination; and iv) presence or absence of comorbidities that affect wound healing. 
 
2.3.2 Closed Fracture Subgroups 
The closed fracture subgroups will be defined by: i) severity of soft tissue injury (Tscherne grade 
3 versus grades 0-2), and ii) presence or absence of comorbidities that affect wound healing.  
 
2.3.3 Subgroup Hypotheses 
It has been established that several patient and injury factors are frequently associated with worse 
patient outcomes after extremity fractures.30,31 As a result, we hypothesize that iodine povacrylex 
(0.7% free iodine) in 74% isopropyl alcohol will be associated with a larger reduction in odds for 
SSI and unplanned fracture-related reoperations among patients with a higher risk for extremity 
fracture SSI.  Specifically, in both the open and closed fracture populations we expect to observe 
this heterogeneity of treatment effect in patients with more severe soft tissue injury and patients 
with increased comorbidities due to the potentially broader antimicrobial coverage, stronger tissue 
adherence, and increased antiseptic longevity of iodine povacrylex.32 The credibility of all 
subgroup analyses will be assessed in accordance with criteria outlined by Sun et al.33 
 
Within the open fracture population, high-grade soft tissue injury (Gustilo-Anderson type III), 
lower extremity open fractures, and moderate/severe wound contamination are established 
predictors of SSI and reoperations from the FLOW trial.5 In addition, there are known differences 
in patients’ skin flora based on anatomic region of injury. As a result, it is likely that the study 
interventions may be more effective in certain open fracture subgroups. Due to its broader 
spectrum of antimicrobial activity, the increased effectiveness observed by Swenson et al., and the 
possible benefits observed in the FLOW trial, we hypothesize that the iodine povacrylex (0.7% 
free iodine) in 74% isopropyl alcohol antiseptic skin solution will be associated with a larger 

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reduction in odds for SSI and reoperation in open fracture patients with Gustilo-Anderson type III 
fractures, lower extremity fractures, and more severely contaminated wounds. 
 
3.0 TRIAL DESIGN 
 
3.1 Summary 
This study is a multi-center pragmatic cluster randomized crossover trial with two independent 
populations of surgically treated fracture participants: 1) the open fracture population consisting 
of a minimum of 1,540 participants with open extremity fractures; and, 2) the closed fracture 
population of a minimum of 6,280 participants with closed lower extremity or pelvic fractures. 
The unit of randomization is the orthopaedic practices within clinical sites (clusters), with 
individual patients being the unit of analysis. The procedures for enrollment, study interventions, 
follow-up, and analyses within the open and closed fracture populations will follow the same 
protocol (with noted differences as applicable). Recruitment for each treatment group will be 
performed in multiple iterations of approximately two-month periods. Each orthopaedic practice 
will initially be randomized to use one of two pre-operative surgical skin preparation solutions 
(iodine povacrylex (0.7% free iodine) in 74% isopropyl alcohol versus 2% CHG in 70% isopropyl 
alcohol) for open and closed extremity fracture surgeries at their institution (Figure 2). Upon 
completion of the two-month period, each orthopaedic practice will crossover to the alternative 
treatment allocation and complete another two-month recruitment period. This process of 
alternating treatment periods (crossovers) will continue until the minimum sample size is achieved 
for each fracture population and the study’s budgeted recruitment duration is completed.  
 
Upon completion of recruitment, it is expected that each orthopaedic practice will enroll a 
minimum of 77 open fracture patients and 314 closed lower extremity or pelvic fracture patients 
per treatment (a minimum of 154 open fracture patients and 628 closed lower extremity or pelvic 
fracture patients in total) as applicable, and that most clinical sites will exceed this minimum 
recruitment goal. Clinical site personnel will screen potential patients for eligibility, and if eligible, 
they will be invited to participate in the trial. Study participants will be assessed at regular intervals 
in the one year following their fracture. The primary outcome will include any SSI event from the 
time of fracture to the end of the 30- and 90-day post-operative periods from their definitive 
fracture management surgery. The secondary outcome will include unplanned fracture-related 
reoperations that occur within one-year of their fracture. A blinded Adjudication Committee will 
review SSIs and unplanned fracture-related reoperations to confirm that they meet the criteria for 
being a study event.  
 
 
Figure 2: Randomized Treatment Allocation, Cluster Crossover, and Recruitment 

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3.2 Pragmatic-Explanatory Continuum 
In accordance with recommended methodology standards, we have used the PRagmatic-
Explanatory Continuum Indicator Summary (PRECIS-2) toolkit to evaluate the PREPARE trial 
design decisions to determine whether these decisions will lead to a study that answers, “Does this 
intervention work under usual conditions?” (pragmatic) versus “Can this intervention work under 
ideal conditions?” (explanatory). The PRECIS-2 tool uses a 5-point Likert scale in 9 domains to 
evaluate the continuum of design choices. A domain score of 5 indicates “very pragmatic,” while 
a score of 1 suggests “very explanatory.” Table 1 outlines the investigators’ assessment of the trial 
design and the rationale for each assessed score and Figure 3 displays the PRECIS-2 wheel. 
 
Table 1: PRECIS-2 Score 
Domain 
Score 
Rationale 
Eligibility 
5 
Eligibility criteria are very broad and include all fracture patients that would be 
treated in all hospital environments. 
Recruitment 
5 
Recruitment of all consenting fracture patients treated at each participating 
hospital will be performed. 
Setting 
4 
Recruitment is occurring at multiple sites across the US and Canada; however, 
since most of the recruiting hospitals are regional referral centers the setting is 
“mostly pragmatic.” 
Organization 
5 
The interventions do not need an increase in providers or care delivery 
compared to the usual antiseptic care provided. For each antiseptic solution, a 
brief in-service training session will be provided to the clinical sites, as per any 
new product/procedure that is being introduced into an operating room. 
Flexibility (delivery) 
5 
The interventions will be delivered in the usual care manner with no advice on 
allowed co-interventions or strict protocols to ensure compliance. 
Flexibility (adherence) 
- 
This section is left blank according to PRECIS-2 guidance because the 
intervention is provided prior to patient consent and individual patient 
compliance is not an issue. If provider adherence is considered, the study design 
is rather pragmatic (4) because there will be limited encouragement to follow 
the manufacturer’s directions for use, other than periodic newsletters, 
investigator meetings, and possible provider survey during the recruitment 
period. 
Follow-up 
5 
All study follow-up is consistent with usual care. 
Primary outcome 
5 
The outcome has been validated by patients as being very relevant to the study 
participants and it does not require specialized expertise beyond the treating 
physician for diagnosis. 
Primary analysis 
5 
All available study data will be used for analysis following the intention to treat 
principle. 
 
 
 

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Figure 3: PRECIS-2 Wheel 
 
4.0 METHODS 
 
4.1 Study Setting, Cluster Eligibility, and Selection of Clusters 
This study will be coordinated by the Methods Center at the Center for Evidence-Based 
Orthopaedics (CEO), McMaster University, Hamilton, Ontario and by the Administrative Center 
within the Department of Orthopaedics at the University of Maryland School of Medicine, R 
Adams Cowley Shock Trauma Center, Baltimore, Maryland. Patients will be enrolled from at least 
18 clinical sites in North America. Clusters (orthopaedic practices within clinical sites) will be 
carefully screened prior to participation in the PREPARE trial. Clinical site inclusion criteria are: 
1) adequate research personnel infrastructure to manage the study; 2) adequate open fracture 
volume and closed lower extremity and pelvic fracture volume to complete enrollment within the 
study timeline (i.e., a minimum of 77 open fractures and 314 closed lower extremity fractures per 
year); 3) commitment from all or most orthopaedic surgeons to participate in the trial; and 4) ability 
to use the two alcohol-based skin preparation solutions. The exclusion criteria are: 1) lack of 
interest in the trial; 2) anticipated challenges with complying with the protocol; 3) conflicting 
studies, in the judgment of the Principal Investigators, that would inhibit patient participation; and 
4) budgeting or contract constraints.  
 
The screening process will begin with potential clinical sites completing a feasibility questionnaire 
that asks about research experience and infrastructure, fracture volume, current practice patterns, 
and interest in participating in the trial. Clinical sites that meet the eligibility criteria at this stage 
will be invited to participate in a series of teleconferences to review study and clinical logistics in 
detail with members of the study team. The Principal Investigators and study personnel will further 

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vet the clinical sites during these calls and will ask about hospital and patient demographics to 
ensure that a variety of fracture patient populations and referral patterns, ranging from large urban 
trauma centers to smaller referral hospitals, are included in the PREPARE trial. Study personnel 
will document reasons for clinical site ineligibility. Upon selection, clinical sites will be asked to 
complete a questionnaire that will detail current surgeon preferences and practices for pre-
operative surgical preparation techniques and co-interventions known to influence the incidence 
of SSIs (see Section 4.7). 
 
4.2 Eligibility Criteria 
Broad eligibility criteria will be used to increase the generalizability of the trial.  Potential 
participants will be enrolled into only one of the study populations depending on whether they 
meet the open or closed fracture population criteria (Section 4.2.1 or 4.2.2).  Participants who meet 
the initial criteria for both populations will be assigned to a study population based on the criteria 
outlined in Section 4.2.3. 
 
4.2.1 Open Fracture Population Eligibility Criteria  
The open fracture inclusion criteria are: 
1. Patients 18 years of age or older. 
2. Open fracture of the appendicular skeleton. 
3. Received or will receive definitive fracture treatment with a surgical implant(s) (i.e., 
internal fixation, external fixation, joint prosthesis, etc.). 
4. Open fracture wound management that includes formal surgical debridement within 72 
hours of their injury. 
5. Will have all planned fracture care surgeries performed by a participating surgeon or 
delegate. 
6. Informed consent obtained. 
7. Patient enrolled within 3 weeks of their fracture. 
 
The open fracture exclusion criteria are: 
1. Fracture of the hand (distal to radial carpal joint). 
2. Patients who did not or will not receive the allocated pre-operative surgical preparation 
solution due to a medical contraindication. 
3. Received previous surgical debridement or management of their fracture at a non-
participating hospital or clinic (as applicable). 
4. Open fracture managed outside of the participating orthopaedic service (e.g., foot fracture 
managed by podiatrist).  
5. Chronic or acute infection at or near the fracture site at the time of initial fracture surgery. 
6. Burns at the fracture site. 
7. Incarceration. 
8. Expected injury survival of less than 90 days. 
9. Terminal illness with expected survival less than 90 days. 
10. Currently enrolled in a study that does not permit co-enrollment. 
11. Unable to obtain informed consent due to language barriers. 
12. Likely problems, in the judgment of study personnel, with maintaining follow-up with the 
patient. 
13. Prior or current enrollment in a PREP-IT trial. 
14. Enrolled in the PREPARE closed cohort. 
15. Excluded due to sampling strategy. 

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4.2.2 Closed Fracture Population Eligibility Criteria 
The closed fracture inclusion criteria are: 
1. Patients 18 years of age or older. 
2. Closed fracture of the lower extremity or pelvis. 
3. Received or will receive definitive fracture treatment with a surgical implant(s) (i.e., 
internal fixation, external fixation, joint prosthesis, etc.). 
4. Fracture management requires a surgical incision (i.e., for fracture reduction or implant 
insertion).  
5. Will have all planned fracture care surgeries performed by a participating surgeon or 
delegate. 
6. Informed consent obtained. 
7. Patient enrolled within 6 weeks of their fracture. 
 
The closed fracture exclusion criteria are: 
1. Patients who did not or will not receive the allocated pre-operative surgical preparation 
solution due to a medical contraindication. 
2. Received previous surgical management of their fracture at a non-participating hospital or 
clinic. 
3. Fracture managed outside of the participating orthopaedic service (e.g., foot fracture 
managed by podiatrist).  
4. Chronic or acute infection at or near the fracture site at the time of initial fracture surgery. 
5. Burns at the fracture site. 
6. Incarceration. 
7. Expected injury survival of less than 90 days. 
8. Terminal illness with expected survival less than 90 days. 
9. Currently enrolled in a study that does not permit co-enrollment. 
10. Unable to obtain informed consent due to language barriers. 
11. Likely, problems, in the judgment of study personnel, with maintaining follow-up with the 
patient. 
12. Prior or current enrollment in a PREP-IT trial. 
13. Enrolled in the PREPARE open cohort. 
14. Excluded due to sampling strategy. 
 
4.2.3 Additional Eligibility Considerations 
1. Patients with multiple fractures will be eligible for inclusion.  
a. In patients with one or more open and one or more closed fractures, study personnel 
will determine whether the participant will be enrolled in the open or closed fracture 
population. This will be determined by identifying the fracture with the highest 
anticipated risk of SSI. In most cases, the open fracture will be selected, and the 
participant will be designated to the open fracture population; however, it is 
possible that a closed lower extremity fracture may have a higher anticipated SSI 
risk compared to an open fracture. A plausible example would be a Tscherne grade 
3 closed intra-articular distal tibia fracture versus a Gustilo-Anderson type I open 
distal radius fracture. 
b. Once the participant is designated to the applicable open or closed fracture 
population, study personnel will collect data on up to three eligible fracture regions.  
If a participant is in the open fracture population, then only eligible regions with 

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open fractures will be included. Similarly, only closed lower extremity or pelvic 
fracture regions will be included if the participant is in the closed fracture 
population. In patients with more than three eligible fracture regions, the treating 
surgeon will determine the three regions with the most severe fractures.   
c. For each fracture, the entire injured anatomic region will be included.34 Therefore, 
if there are two fractures that anatomically communicate, they will be considered 
within the same region (e.g., within the shoulder region, forearm, etc.). For open 
fracture participants, adjacent closed fractures that anatomically communicate with 
an open fracture or are treated within the same surgical incision will be included in 
the open fracture region. Common examples of these include forearm fractures, 
tibia/fibula fractures, and peri-articular fractures. The anatomic joint region, 
adjacent fractures, and contiguous wounds will be defined at the time of patient 
enrollment on the case report forms (CRFs).  
d. All included fracture regions should be treated with the same allocated antiseptic 
skin solution as per the cluster randomization.    
2. At the time of screening, patients who are in another study who meet eligibility criteria are 
to be included in the PREPARE trial unless the other trial does not permit co-enrollment. 
3. Closed fractures that are definitively managed without a surgical incision will be excluded 
(e.g., stab incisions and pin sites) because a localized stab wound or pin site infection does 
not meet the CDC definition for SSI. If there is an associated surgical incision, these 
fractures will be included (e.g., open reduction and fixation with an external fixator, k-
wires, etc.). 
 
4.3 Recruitment Strategy  
4.3.1 Patient Screening & Consent 
Patients 18 years of age or older who present to a recruiting hospital for treatment of an open 
fracture of the appendicular skeleton will be screened for participation within 3 weeks of their 
fracture. Patients 18 years of age or older who present to a recruiting hospital for surgical treatment 
of a closed lower extremity or pelvic fracture(s) will be screened for participation within 6 weeks 
of their fracture.  To screen patients for eligibility, designated study personnel at each clinical site 
will develop a patient enrollment plan. This plan will typically consist of daily participation in 
orthopaedic patient rounds and a review of daily listings of hospital admissions for patients with open 
fractures and or closed lower extremity or pelvic fractures. Upon identification, the study personnel 
will screen the patient for eligibility and if eligible, approach them for informed consent. Study 
participants with open fractures must be enrolled within 3 weeks of their fracture(s) and study 
participants with closed fractures must be enrolled within 6 weeks of their fracture(s).  Enrollment 
may take place at any time within this window.  If the patient is unable to provide informed consent 
(e.g., due to their injury) at the time they were initially identified, informed consent may be delayed 
until they are able to provide informed consent. Alternatively, if the patient is unable to provide 
informed consent, informed consent may be obtained from their proxy, with consent obtained from 
the patient when/if the patient is able to provide consent. Allowing informed consent from a patient’s 
proxy healthcare decision maker will reduce the risk of recruitment bias against the most severely 
injured patients. In addition, potentially eligible patients will be approached to participate in the 
trial, even if they did not receive the correct pre-operative antiseptic skin solution. This is 
consistent with the ITT principle and is necessary to maintain the prognostic balance achieved 
during the cluster randomization. All screened patients will be classified as included, excluded, or 
missed. See Table 2 below for the Schedule of Events. 
 

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Table 2: Schedule of Events 
Assessment 
Visit 1: 
Enrollment 
Visit 2: 
6 weeks post-
fracture 
Visit 3: 
3 months  
post-fracture 
Visit 4: 
6 months  
post-fracture 
Visit 5: 
9 months  
post-fracture 
Visit 6 
12 months  
post-fracture 
Eligibility 
Screening  
● 
 
 
 
 
 
Informed 
Consent  
● 
 
 
 
 
 
Collection of 
Demographic 
and Fracture 
Characteristics 
Data 
● 
 
 
 
 
 
Collection of 
Surgical Data 
● 
 
 
 
 
 
Collection of 
Peri-Operative 
Data 
● 
 
 
 
 
 
Collection SSI 
Data 
● 
● 
● 
● 
● 
● 
Collection of 
Reoperation 
Data 
● 
● 
● 
● 
● 
● 
Collection of 
SAE Data 
● 
● 
● 
● 
● 
● 
For patients with open fractures, informed consent and enrollment must occur within the 3 weeks (21 days) from the 
patient’s fracture (Day 0 is the date of the fracture). For patients with closed fractures, informed consent and 
enrollment must occur within the 6 weeks (42 days) from the patient’s fracture (Day 0 is the date of the fracture). 
Visits are to be completed at routine clinic visits. When necessary, visits may also be completed by telephone, text, 
email, standard mail, and/or a review of the participant’s medical record.  
Follow-up visit windows touch so that participants will always fall into a specific window.  The windows are: 4 to 8 
weeks (i.e., 28 to 56 days), 2 to 4.5 months (i.e., 57 to 137 days), 4.5 to 7.5 months (i.e., 138 to 228 days), 7.5 to 12 
months (i.e., 229 to 365 days), and greater than 12 months (366 to 730 days), respectively, from the participant’s 
fracture. 
 
4.4 Managing Patient Volume  
When the volume of eligible patients exceeds a participating site’s ability to effectively enroll and 
follow all eligible patients, two strategies are available to manage patient volume and ensure that 
enrollment targets are met.  Clinical sites may obtain permission from the Methods Centre to use 
either one or both of these strategies. 
 
4.4.1 Enrollment of Patients from Only One Fracture Cohort 
To manage patient volume, clinical sites may obtain permission from the Methods Centre to only 
enroll patients from one fracture cohort (i.e., open fracture cohort or closed fracture cohort), as 
opposed to both.  When this strategy is used, clinical sites will only approach patients from the 
fracture population selected (i.e., they will only enroll patients with open fractures or only enroll 
patients with closed fractures).  The Methods Centre will work with clinical sites to determine the 
fracture population from which patients should be recruited.  Additionally, sites with competing 
studies may also enroll into one fracture cohort only.  For example, clinical sites who are 
participating in the Aqueous-PREP trial (sister trial to PREPARE), may participate in PREPARE 
by enrolling patients into the closed fracture cohort alone. 
 

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4.4.2 Enrollment Sampling Plan 
A sampling strategy is available within the REDCap Cloud electronic data capture (EDC) system 
which will randomly determine whether an eligible patient should be approached for consent and 
inclusion in the study. The randomization software will use randomly selected block sizes 
consistent with the sampling ratio being used during the recruitment periods. Examples of potential 
random sampling strategies a site may use include:  
 
1. 
For every three eligible patients, there will be one excluded eligible patient (3:1 ratio). 
2. 
For every two eligible patients, there will be one excluded eligible patient (2:1 ratio). 
3. 
For each eligible patient, there will be one excluded eligible patient (1:1 ratio). 
4. 
For each eligible patient, there will be two excluded eligible patients (1:2 ratio).  
5. 
For each eligible patient, there will be three excluded eligible patients (1:3 ratio). 
 
The number of eligible patients approached for consent and inclusion in the study, and the number 
of eligible patients that are excluded due to a sampling strategy will be documented in the EDC 
system. 
 
For sites enrolling patients from both open and closed fracture populations, the enrollment 
sampling plan may differ between the open and closed fracture populations.  Therefore, it is 
possible that a recruiting cluster may achieve their overall enrollment goal sooner in one 
population than the other. If this occurs, Methods Center personnel may instruct the recruiting 
cluster to stop enrollment of the completed population and continue enrollment of only the other 
fracture population.  This decision will be made based on the overall study recruitment, timelines, 
and other logistical concerns. 
 
4.4 Randomization Methods  
Treatment allocation will be determined using a cluster-randomized crossover trial design. The 
order of treatment allocation for each orthopaedic practice (cluster) will be randomly assigned 
using a computer-generated randomization table. Each site will start with the initially allocated 
study solution and crossover to the other solution for their second recruitment period. Both the 
open fracture and closed lower extremity and pelvic fracture populations will receive the same 
treatment allocation and follow the same crossover schedule. The process of alternating treatments 
will repeat approximately every two months as dictated by the initial randomization.  For sites that 
enroll for more than 1 year, the order of treatment allocation may be reversed after 12 months to 
ensure equal distribution of each treatment across each calendar month in the study’s duration 
(Figure 2). Randomization will be completed by personnel at the CEO Methods Center at the onset 
of the trial. Personnel from the Methods Center will notify personnel at each participating clinical 
site of their treatment allocation order. This will allow each participating clinical site to begin 
preparing for the first run-in period. 
 
4.5 Blinding 
The orthopaedic team (including the study coordinators) cannot be blinded to the treatment 
allocation as the antiseptic solutions are visually distinguishable and these individuals need to lead 
the implementation of the cluster-crossover protocol at their clinical site. The Adjudication 
Committee Members and data analysts will be blinded to the study treatment. All interpretations 
of study results will initially be done in a blinded manner by developing two interpretations of the 
results. One interpretation will assume treatment A is iodine povacrylex (0.7% free iodine) in 74% 
isopropyl alcohol, the other interpretation will assume it is 2% CHG in 70% isopropyl alcohol. 

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Once the data interpretations for each assumption are finalized, the data will be unblinded and the 
correct interpretation will be accepted.35  
 
4.6 Description of the Interventions  
4.6.1 Initial Run-In Phase 
Prior to initiating patient recruitment, each clinical site will begin using their assigned pre-
operative antiseptic skin solution for eligible fracture surgeries (run-in period) to ensure that 
acceptable compliance is met before initiating participant enrollment. Acceptable compliance 
during the run-in phase will be defined as at least 15 eligible open fracture patients and at least 15 
closed lower extremity or pelvic fractures patients with >90% of eligible patients receiving the 
allocated antiseptic solution or a minimum of one month in duration. The run-in phase may be 
extended up to 3 months, as deemed necessary by the CEO Methods Center. Study personnel at 
each clinical site will document compliance with administering the allocated treatment during the 
run-in phase and submit this weekly to the CEO Methods Center. Specifically, the weekly reports 
will include the total number of eligible operative patients within the open fracture population and 
the closed fracture population, the proportion who received the assigned pre-operative antiseptic 
skin solution, and the proportion who did not receive the assigned pre-operative antiseptic skin 
solution along with details about the deviations (e.g., name of attending surgeon, solution used, 
rationale for not using the assigned pre-operative antiseptic skin solution). This portion of the study 
protocol is for quality assurance during the initial implementation of the trial procedures.  Fracture 
surgeries reviewed during the run-in phase will not be included in the trial.  Similarly, these 
patients will not be approached for informed consent and no individual patient-level data will be 
submitted. CEO Methods Center personnel will review the weekly reports with each of the clinical 
sites and develop strategies, as needed, to ensure acceptable compliance during the run-in phase. 
This weekly communication will prevent any delays in transitioning to the participant enrollment 
phase.  
 
4.6.2 First Intervention Phase 
Once the initial run-in phase is completed, participant recruitment will begin with the clinical sites 
continuing to use the same pre-operative antiseptic skin solution for all eligible fracture surgeries 
within the open and closed fracture populations over a two-month period. Patients will receive the 
initially allocated treatment solution for all of their fracture management surgeries, including 
repeat planned surgeries, even if a planned subsequent surgery occurs during a recruitment period 
using the non-allocated solution. Participating clusters will ideally be able to enroll a minimum of 
77 open fracture patients and 314 closed lower extremity and pelvic fractures per treatment over 
the total study recruitment duration (total of 154 open fracture patients and 628 closed lower 
extremity and pelvic fracture patients), and it is anticipated that most recruiting centers will exceed 
this minimum goal. Methods Center personnel will continue to monitor compliance with the 
assigned pre-operative antiseptic skin solution over the enrollment phase and work collaboratively 
with the clinical sites to minimize cases in which a patient receives the incorrect solution. These 
monitoring activities will coincide with site-specific procedures to maintain compliance for all 
patients, even those requiring multiple surgical procedures. All assessments of compliance will be 
analyzed separately for the open and closed fracture populations. If a fracture requires multiple 
surgeries and the correct solution is not applied at each procedure, the patient will remain in the 
study and be analyzed using the allocated solution (ITT principle). 
 

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4.6.3 Second Intervention Phase  
Once the first intervention phase is completed, each site will crossover to the opposite study 
solution. This crossover will occur simultaneously in the open and closed fracture populations. 
There will be no run-in phase for the second solution and each site will need to develop local 
procedures to ensure a successful crossover. Example procedures to minimize carry-forward of 
first solution into the second solution phase include: 1) removing the bottles of the first solution 
from the orthopaedic operating rooms; 2) changing study posters and notifications within the 
operating rooms; and 3) performing the crossover during the middle of the week to provide a few 
days’ notice to the operating room staff and to avoid contamination of recent fracture patients 
returning for repeat procedures (e.g., weekend admissions). The enrollment goals and procedures 
will mirror the first intervention phase. Methods Center personnel will continue to monitor 
compliance with the assigned pre-operative antiseptic skin solution over the enrollment phase and 
work collaboratively with the clinical sites to reduce the risk of contamination.  
 
4.6.4 Special Considerations for Ongoing Treatment Crossovers 
Treatment allocation will continue to alternate between the study solutions, as outlined above, for 
the remainder of study duration. Each intervention phase will be approximately two months in 
duration, as agreed upon by the clinical site and CEO Methods Center personnel. The duration 
may be modified to avoid crossovers on holidays, weekends, and other circumstances that could 
threaten a successful crossover. The expected recruitment duration for the trial is approximately 
24 months; however, some sites may have a shorter total recruitment duration (e.g., a participating 
site that joins the trial later, high volume clinical sites, etc.). The two-month enrollment periods 
will help account for seasonal variability in SSI incidence and their associated infectious 
organisms,36 as each crossover period will cover a season. In addition, for those clinical sites 
enrolling beyond 12 months, the distribution of recruitment periods for each solution may be 
seasonally matched by reversing the order of the alternating allocation after 12 months of 
recruitment.  
 
4.6.5 Evaluation of Site Performance and Removal of Clinical Sites 
After every two recruitment periods (approximately every four months), each site will be evaluated 
for continued participation in the trial. Sites with <90% of eligible patients receiving the allocated 
solution, differential adherence between study solutions, <95% follow-up of the primary outcome, 
<90% follow-up of the secondary outcome, incomplete data submission, or other threats to data 
quality or the validity of the study may be withdrawn from the trial. In the event a site is withdrawn, 
data collection will be completed for all enrolled participants and these data will be included in the 
final study analysis. 
 
4.6.6 Application of Pre-Operative Antiseptic Skin Solutions 
Each solution will be applied to the skin and allowed to dry for a minimum of three minutes. While 
the application and minimum drying time for both study solutions are very similar, local study 
personnel will provide standardized in-service (training) for orthopaedic surgeons, operating room 
technicians, and nurses at each participating hospital prior to the initial run-in phase.  This training 
should include reviewing the manufacturers’ directions for use to help minimize incorrect 
application at clinical sites that may not routinely use both solutions. In addition, the manufacturers 
may also provide demonstration videos and posters for continued refresher training for each 
solution.  
 

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The study protocol will mandate the antiseptic skin solution to be used in each intervention phase 
(Sections 4.4, 4.6.1, 4.6.2, 4.6.3, and 4.6.4); however, the protocol will remain pragmatic to 
variability in the actual application of the solutions and other co-intervention steps performed 
during the entire pre-operative skin preparation process performed in the operating room. Based 
on individual surgeon preference, this often includes mechanically removing visible dirt or debris 
with a scrub brush, and/or cleaning the limb with isopropyl alcohol or an antiseptic scrub solution. 
These additional skin preparation steps will be permitted provided that: 1) the final skin 
preparation step prior to surgical incision is the application of the allocated antiseptic solution; 
and, 2) participating surgeons continue to use the same skin preparation co-interventions in both 
intervention phases.  Co-interventions that contain the opposite active ingredient from the current 
intervention phase (e.g., using a CHG scrub brush during the iodine intervention phase, or 
conversely, using an iodine scrub during the CHG intervention phase) should be avoided; however, 
deviations from this recommendation will be permitted to maintain pragmatic flexibility of delivery 
and reflect real-world clinical practice. The details of all operating room antiseptic co-interventions 
will be documented. 
 
4.6.7 Patients with Multiple Planned Surgeries 
Fracture patients who require multiple planned surgeries for their injury will receive the same 
antiseptic skin solution during each subsequent procedure. Methods Center personnel will work 
with each of the clinical sites to develop strategies for minimizing crossovers. For example, for 
patients who require multiple surgeries and are enrolled within 14 days of the anticipated end of a 
recruitment period, study personnel will develop local procedures to identify these patients as 
study participants and indicate the patient’s allocated antiseptic solution in the medical chart and 
CRFs.  
 
4.6.8 Iodophor Antiseptic Solution 
The iodine-based treatment intervention will be an antiseptic solution comprised of iodine 
povacrylex (0.7% free iodine) in 74% isopropyl alcohol. 3M™ DuraPrep™ [3M Health Care, St 
Paul, MN], will be the commercial product used. Clinical site personnel will store and handle the 
product as per the manufacturers’ recommendations. Operating room personnel will apply the 
solution to the operative site as the final preoperative skin antisepsis preparation immediately prior 
to commencing surgical fixation. They will apply the solution as per manufacturer’s directions for 
use (e.g., technique of application, duration of application, drying time, drying techniques, 
replacement of draping, etc.).  
  
4.6.9 CHG Antiseptic Solution 
The CHG solution will contain 2% CHG in 70% isopropyl alcohol as the only active ingredients. 
Products that list other inactive ingredients will be permitted. ChloraPrep® [CareFusion Inc., 
Leawood, KS, USA] will be the commercial product used. Clinical site personnel will store and 
handle the product as per the manufacturers’ recommendations. Operating room personnel will 
apply the solution to the operative site as the final preoperative skin antisepsis preparation 
immediately prior to commencing surgical fixation. They will apply the solution as per 
manufacturer’s directions (e.g., technique of application, duration of application, drying time, 
replacement of draping, etc.).  
 
4.7 Perioperative Co-Interventions 
To optimize the internal validity of the trial findings, key details of co-interventions known to 
influence the incidence of SSIs will be documented. Hospitals typically implement standard 

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procedures to achieve quality process benchmarks designed to minimize SSIs. These benchmarks 
are outlined in several similar guidelines such as the Joint Commission’s Surgical Care 
Improvement Project 10 Core Measures to prevent SSI, the Society for Healthcare Epidemiology 
of America compendium to prevent SSI, and prevention guides from the Institute for Healthcare 
Improvement and the Association of periOperative Registered Nurses. While these guidelines 
mandate core benchmark processes to minimize SSI, it is not practical or generalizable for the trial 
protocol to standardize the steps taken or co-interventions performed to achieve these core 
measures, since each participating hospital will already have their own implemented procedures. 
This is the primary rationale for the cluster-crossover design, in which each participating hospital 
will act as its own control for the effect of co-interventions. Therefore, four key approaches to 
account for and limit the potential differential application of co-interventions during the study 
periods will be performed: 1) study periods for each intervention are kept relatively short to 
improve the likelihood that newly implemented co-interventions will be equally distributed across 
both treatment solutions; 2) encourage participating hospitals not to make changes to their existing 
infection prevention interventions during the study periods; 3) document the co-interventions 
being used in the hospitals throughout the study periods; and 4) record any changes in co-
interventions that do occur if mandated by a participating hospital’s administration. To this end, a 
monitoring tool containing a list of commonly applied prophylactic co-interventions being used at 
the participating clinical sites will be completed approximately every four months to document 
any changes to their infection prevention strategies during the study period. 
 
4.8 Outcome Measures 
4.8.1 Primary Outcome  
The primary outcome is SSI, guided by the CDC’s National Healthcare Safety Network reporting 
criteria (2017),25 which includes superficial incisional SSI within 30 days and deep incisional or 
organ/space SSI within 90 days of fracture surgery (Table 3). Since the management of some 
fractures may have more than one operative procedure as part of an intentionally staged surgical 
plan (e.g., multiple irrigation and debridements, wound closures, temporary stabilization surgeries, 
definitive fixation surgery), the primary outcome will include any SSI event from the date of 
fracture to the end of the 30- and 90-day post-operative surveillance periods from their definitive 
fracture management surgery. For participants with multiple fracture regions, the date of the 
definitive fracture management surgery will be matched to the fracture region with the SSI. 
 
Table 3: CDC Surgical Site Infection Criteria 
Outcome 
Description 
Superficial 
Incisional 
SSI 
Date of event for infection occurs from the date of fracture to 30 days after the definitive fracture 
management surgery (where day 1 = the procedure date) 
AND 
involves only skin and subcutaneous tissue of the incision 
AND 
patient has at least one of the following: 
a. 
purulent drainage from the superficial incision. 
b. organisms identified from an aseptically-obtained specimen from the superficial 
incision or subcutaneous tissue by a culture or non-culture based microbiologic 
testing method which is performed for purposes of clinical diagnosis or 
treatment (e.g., not Active Surveillance Culture/Testing [ASC/AST]). 
c. 
superficial incision that is deliberately opened by a surgeon, attending physician 
or other designee and culture or non-culture based testing is not performed. 
              AND 

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Outcome 
Description 
patient has at least one of the following signs or symptoms: pain or tenderness; 
localized swelling; erythema; or heat. 
d. diagnosis of a superficial incisional SSI by the surgeon or attending physician 
or other designee.  
The following do not qualify as criteria for meeting the definition of superficial SSI: 
• 
Diagnosis/treatment of cellulitis (redness/warmth/swelling), by itself, does not meet 
criterion “d” for superficial incisional SSI. Conversely, an incision that is draining or that 
has organisms identified by culture or non-culture based testing is not considered a 
cellulitis. 
• 
A stitch abscess alone (minimal inflammation and discharge confined to the points of 
suture penetration). 
• 
A localized stab wound or pin site infection- Such an infection might be considered either 
a skin (SKIN) or soft tissue (ST) infection, depending on its depth, but not an SSI  
Note: A laparoscopic trocar site for an operative procedure is not considered a stab wound. 
• 
An infected burn wound is classified as BURN and is not an SSI. 
Deep 
Incisional 
SSI 
The date of event for infection occurs from the date of fracture to 90 days after the definitive 
fracture management surgery (where day 1 = the procedure date)  
AND 
involves deep soft tissues of the incision (e.g., fascial and muscle layers) 
AND 
patient has at least one of the following: 
a. 
purulent drainage from the deep incision. 
b. a deep incision that spontaneously dehisces, or is deliberately opened or aspirated by a 
surgeon, attending physician or other designee, and organism is identified by a culture or 
non-culture based microbiologic testing method which is performed for purposes of 
clinical diagnosis or treatment (e.g., not Active Surveillance Culture/Testing 
[ASC/AST]) or culture or non-culture based microbiologic testing method is not 
performed 
            AND 
patient has at least one of the following signs or symptoms: fever (>38°C); localized 
pain or tenderness. A culture or non-culture based test that has a negative finding does 
not meet this criterion. 
c. 
an abscess or other evidence of infection involving the deep incision that is detected on 
gross anatomical or histopathologic exam, or imaging test 
Organ/Space 
SSI 
Date of event for infection occurs from the date of fracture to 90 days after the definitive fracture 
management surgery (where day 1 = the procedure date)  
AND 
infection involves any part of the body deeper than the fascial/muscle layers, that is opened or 
manipulated during the operative procedure 
AND 
patient has at least one of the following: 
a. 
purulent drainage from a drain that is placed into the organ/space (e.g., closed 
suction drainage system, open drain, T-tube drain, CT guided drainage) 
b. organisms are identified from an aseptically-obtained fluid or tissue in the 
organ/space by a culture or non-culture based microbiologic testing method 
which is performed for purposes of clinical diagnosis or treatment (e.g., not 
Active Surveillance Culture/Testing [ASC/AST]). 
c. 
an abscess or other evidence of infection involving the organ/space that is 
detected on gross anatomical or histopathologic exam, or imaging test evidence 
suggestive of infection. 
AND 
meets at least one criterion for a specific organ/space infection site listed in Table 3 of the CDC 
Procedure-associated Module (summarized in Table 4 below).25 These criteria are found in the 
Surveillance Definitions for Specific Types of Infections chapter.37 
*The CDC criteria has been modified to include all definitive fracture management surgeries, as opposed to including 
only National Healthcare Safety Network procedures that require infection reporting.  

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The CDC criteria for classifying SSIs will be followed. If multiple tissue levels are involved in the 
infection, the type of SSI (superficial incisional, deep incisional, or organ/space) reported will 
reflect the deepest tissue layer involved in the infection during the surveillance period. The date of 
event will be the date that the participant met criteria for the deepest level of infection using the 
following procedures: 1) report infection that involves the organ/space as an organ/space SSI, 
whether or not it also involves the superficial or deep incision sites and 2) report infection that 
involves the superficial and deep incisional sites as a deep incisional SSI. The most relevant 
National Healthcare Safety Network Organ/Space SSI classifications are summarized in Table 4. 
Whenever possible, the treating surgeon or study personnel should take photos of the infected 
region to facilitate the adjudication process. 
 
Table 4: Relevant Organ/Space SSI Sites 
Organ/Space SSI 
BONE 
Osteomyelitis 
JNT 
Joint or bursa infection 
PJI 
Prosthetic joint infection 
 
 
All reported SSIs will be reviewed independently by an infection preventionist nurse and an 
orthopaedic surgeon who are members of the Adjudication Committee. Briefly, they will complete 
the review by examining all relevant information to determine if the SSI meets the CDC criteria 
of a superficial incisional SSI, deep incisional SSI, or organ/space SSI. The Committee will reach 
consensus on all reviewed SSIs. A hospital epidemiologist and infectious disease physician who 
are members of the Adjudication Committee will be available to provide guidance as needed.  All 
members of the Adjudication Committee will be blinded to the treatment allocation.  
 
4.8.2 Secondary Outcome 
The secondary outcome is unplanned fracture-related reoperation within 12 months of the 
fracture(s). This outcome has been used in previous fracture trials and is defined as any unplanned 
surgery that occurred from the time of injury to 12 months post-injury that is associated with an 
infection at the operative site or contiguous to it, a wound-healing problem, or a fracture delayed 
union or nonunion. Common examples include any unplanned: 1) irrigation and debridement of 
surgical incisions or open fracture wounds due to infections or wound healing problems; 2) 
revision wound closure for dehiscence; 3) soft tissue coverage procedure for infected or necrotic 
wound; 4) fracture delayed union or nonunion surgery (such as bone grafting or implant exchange); 
and 5) reoperation for hardware or prosthesis failure due to infection or bone-healing problems. 
Removal of hardware for soft tissue prominence or periprosthetic fracture are common examples 
of reoperations that will not be considered outcome events. To facilitate adjudication, the treating 
surgeon or study personnel should take photographs of any infections or wound infections. Two 
orthopaedic surgeons who are members of the Adjudication Committee will independently review 
all reported unplanned fracture-related reoperations to determine if they meet the criteria for being 
a study event.  The Committee will reach consensus on all reviewed unplanned fracture-related 
reoperations. 
 
4.8.3 Exploratory Outcomes 
Two exploratory definitions of infection will be used for sensitivity analyses of the primary 
comparison. The first exploratory outcome is fracture-related infection (FRI) within 12 months of 
the fracture, defined by the confirmatory criteria for FRI outlined in a 2018 consensus definition.38  
The FRI criteria has been selected as an exploratory outcome because the CDC criteria has been 

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criticized for failing to adequately account for the complexities of infections in traumatic 
fractures.38,39 The FRI criteria attempts to improve upon the ability to detect infections specifically 
in fracture patients; however, this definition of FRI has not been fully validated or widely adopted.    
 
The confirmatory criteria include the presence of one or more of the following signs/symptoms:  
1) Fistula, sinus or wound breakdown (with communication to the bone or the implant). 
2) Purulent drainage from the wound or presence of pus during surgery. 
3) Phenotypically indistinguishable pathogens identified by culture from at least two separate 
deep tissue/implant (including sonication-fluid) specimens taken during an operative 
intervention. In case of tissue, multiple specimens (3) should be taken, each with clean 
instruments (not superficial or sinus tract swabs). In cases of joint effusion, arising in a 
joint adjacent to a fractured bone, fluid samples obtained by sterile puncture may be 
included as a single sample. 
4) Presence of microorganisms in deep tissue taken during an operative intervention, as 
confirmed by histopathological examination using specific staining techniques for bacteria 
or fungi.  
 
The second exploratory outcome is SSI using the CDC criteria within 12 months of the fracture.  
This secondary outcome will use the same diagnostic CDC reporting criteria for the primary 
outcome (Tables 3 and 4); however, the timeframe for this outcome will be expanded to include 
all SSIs that occur within 12 months of fracture.  Similar to the rationale for using the FRI outcome, 
and the recommendations for a minimum of 12 months follow-up for orthopaedic fracture 
outcomes40, this expanded timeframe will detect infections that occur beyond the standard CDC 
surveillance reporting periods.  This modification of the CDC reporting periods has been used in 
previous orthopaedic fracture trials.4,41  
 
An infection preventionist nurse and an orthopaedic surgeon member of the Adjudication 
Committee will review all reported SSIs to determine if they meet the FRI confirmatory criteria 
and / or the CDC criteria following the processes described above (see Section 4.8.1).   
 
4.8.4 Data Collection and Participant Follow-up 
After obtaining informed consent, study personnel will record the baseline data on the study CRFs. 
They will obtain this information directly from the participant or proxy, from the participant’s 
medical chart, and the participant’s treating orthopaedic surgeon or other health care providers. 
Data collection points include participant characteristics and injury details such as age, gender, 
comorbidities, mechanism of injury, and other injuries. Study personnel will also record the 
characteristics of up to three eligible fracture regions including the bone(s) fractured, fracture 
severity, size of the wound (if applicable), and degree of soft tissue injury using the Tscherne 
classification in closed fractures and the Gustilo classification in open fractures.1,34,36   
 
Surgical data and in-hospital data will be collected throughout the participant’s hospital stay. 
Detailed information will be collected regarding the surgical management of their fracture(s), 
including the timing of the surgery(ies) and the method of initial and definitive fracture treatment. 
For open fracture regions, study personnel will also record the use of staged debridements, the 
presence or lack of skin closure between debridements, and the use of local antibiotics at the 
wound. Lastly, study personnel will record the use of negative pressure wound therapy for open 
wounds or in the presence of open wounds surgically closed. These treatment decisions are 

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hypothesized to be associated markers of injury severity and potential confounders of the study 
interventions. 
 
Study participants will be followed at 6 weeks, 3 months, 6 months, 9 months, and 12 months from 
their fracture.  SSIs and unplanned fracture-related reoperations will be identified at the time of 
diagnosis/occurrence and/or during each participant’s clinical assessment and medical record 
review that will occur during their routine outpatient clinic visits (Table 2). Detailed information 
on the SSI including the date of diagnosis, participant signs and symptoms, culture test results, 
method of treatment(s), and date of resolution will be collected. Study personnel will also record 
details about the participants’ reoperations on the CRFs (e.g., date of reoperation, type of 
procedure, reason for procedure, etc.). In cases where the participant does not return to the clinic, 
study personnel will contact the participant by telephone, text, email, and standard mail and will 
review their medical record for any SSIs or fracture-related reoperations. If the participant reports 
being treated at another hospital, study personnel will obtain the medical records from the other 
hospital. We have used this approach in our other multi-center trials (e.g., SPRINT, TRUST, 
FLOW, FAITH, HEALTH, etc.).4,41–44  
 
To ensure research participant safety, serious adverse events (SAEs) will be documented at each 
follow-up visit and promptly submitted to the Methods Center and the local or central Institutional 
Review Board (IRB) or Research Ethics Board (REB) as per the required reporting processes.  
 
Several strategies may be used to maximize follow-up including: 1) at the time of enrollment, each 
participant will provide their own telephone number, as well as the name and address of a primary 
care physician, and the names and phone numbers of three people at different addresses with whom 
the participant does not live with and who are likely to be aware of the participant’s whereabouts; 
2) participants will receive a reminder card upon discharge for their next follow up visit by the 
clinical site study personnel; 3) participants will receive text message reminders; 4) follow-up will 
coincide with normal surgical fracture clinic visits; and 5) if a participant refuses or is unable to 
return for the follow-up assessment, study personnel will determine his/her status with regard to 
major study outcomes by telephone, text, mail, or email contact with the participant or the provided 
alternate contacts. Given these are standard of care visits and the participants will be receiving 
ongoing orthopaedic care for their acute fractures, minimal loss to follow-up is expected. Using 
these techniques, we expect greater than 95% follow-up at 3 months and 90% follow-up at 12 
months post-fracture. 
 
Participants will not be deemed lost to follow-up until the 12-month visit is overdue and all 
attempts to contact the participant have been exhausted. Participants will not be withdrawn from 
the study if the study protocol was not adhered to (e.g., allocated treatment not received, missed 
follow-up visits, etc.). The reasons for participants being withdrawn from the study will be 
documented (e.g., withdrawal of consent or lost to follow up). 
 
5.0 STATISTICAL PLAN  
 
5.1 Sample Size Determination 
The overall objective of the trial is to determine the most effective alcohol-based pre-operative 
antiseptic skin solution for use during extremity fracture management. This objective is being 
performed independently in the open and closed fracture populations. In both fracture populations, 
the analyses will compare the effectiveness of iodine povacrylex (0.7% free iodine) in 74% 

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isopropyl alcohol versus 2% CHG in 70% isopropyl alcohol surgical skin preparations. The 
primary outcome is the occurrence of SSI, as per the adapted CDC criteria (Table 3).25 The 
secondary outcome is the occurrence of unplanned fracture-related reoperations within 12 months 
of injury. Separate sample size estimates for the open and closed fracture populations were 
calculated to facilitate the primary comparison between proportions of patients with SSI in each 
treatment group. It is expected that this estimate will also provide adequate power for the secondary 
outcome (unplanned fracture-related reoperation) because a meaningful effect size for the 
reoperation outcome is expected to be similar to the SSI estimates. Additionally, the baseline risk 
of unplanned reoperations in both fracture populations is expected to be greater than the risk of 
SSI.4  
 
Assuming an ITT principle for the analysis, the sample size was calculated based on a cluster 
crossover design with the cluster as the unit of randomization and the patient as the unit of analysis. 
For complex study designs, such as a cluster-randomized crossover trial, simple formulas to 
calculate sample size or power may not capture the expected variability from the observed data.45 
Simulation methods were used to obtain empirical power calculations based on a feasible number 
of recruiting clusters and the expected number of participants within the open and closed fracture 
populations.45 The simulation estimates are designed to detect a difference between the treatment 
groups, accounting for between hospital variability inherent to a cluster-crossover trial design.  
 
We have estimated the CHG group will experience a SSI incidence of 12.5% in the open fracture 
population and a 3.5% incidence within the closed fracture population.3,4  Compared to CHG, we 
have assumed the iodine povacrylex solution will achieve a 0.65 risk reduction for SSI and 
unplanned fracture-related reoperation in each fracture population.22 This effect was selected as 
the smallest difference that would be important to detect, in the sense that any smaller effect would 
not be of clinical or substantive importance. Additionally, this effect was deemed more 
conservative than data reported by Swenson et al. and was consistent with feasible recruitment 
goals.21   
 
We have based our sample size assumptions using a single crossover, 2-period design to ensure 
the most conservative sample size estimate.  Recent simulation data suggest that increasing the 
number of period crossovers can increase the statistical power of a given sample size.46 The initial 
power estimate assumed 10 recruiting clusters, a 10% loss to follow-up rate,4 and applying the 
between-cluster variance of 0.095 observed in the FLOW trial.  Based on enrollment of a minimum 
of 1,540 open fracture patients and 6,280 closed lower extremity and pelvic fractures, greater than 
80% power would be achieved for each fracture population. Subsequent to the initial power 
calculations, the early trial experience demonstrated a need to increase the number of clusters to 
obtain a feasible recruitment pace. As a result, a minimum 18 clusters will enroll participants into 
PREPARE. The increase in clusters results in a marginal increase in power (~2%).   
 
Table 5 and Table 6 below outlines the summary of the initial sample size assumptions. These 
sample size estimates are rounded up to the nearest multiple of 20 to ensure balance among 10 
clinical sites and two interventions. 
 
Table 5: Sample Size Assumptions for Open Fractures 
Baseline SSI Risk 
Iodine Risk Ratio 
Iodine Odds Ratio 
Sample Size 
Sample Size Increased 
by 10% 

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10.0% 
0.62 
0.59 
1,600 
1,760 
10.0% 
0.65 
0.63 
1,960 
2,100 
10.0% 
0.67 
0.65 
2,200 
2,420 
10.0% 
0.70 
0.68 
2,600 
2,860 
12.5% 
0.62 
0.59 
1,300 
1,440 
12.5% 
0.65 
0.62 
1,400 
1,540 
12.5% 
0.67 
0.64 
1,600 
1,760 
12.5% 
0.70 
0.67 
1,800 
1,980 
14.0% 
0.62 
0.58 
1,200 
1,320 
14.0% 
0.65 
0.61 
1,300 
1,440 
14.0% 
0.67 
0.64 
1,500 
1,660 
14.0% 
0.70 
0.67 
1,800 
1,980 
Note: Between cluster ICC = 0.028; Between cluster variance = 0.095; Between period variance = 0; Number of 
clusters = 10; Number of periods = 2; Alpha = 0.05 
 
Table 6: Sample Size Assumptions for Closed Fractures of the Lower Extremity  
Baseline SSI Risk 
Iodine Relative 
Risk 
Iodine Odds Ratio 
Sample size 
Sample Size increased 
by 10% 
2% 
0.62 
0.62 
8,200 
9,020 
2% 
0.65 
0.65 
10,000 
11,000 
2% 
0.67 
0.67 
11,400 
12,540 
3.5% 
0.62 
0.61 
4,700 
5,170 
3.5% 
0.65 
0.64 
5,700 
6,280 
3.5% 
0.67 
0.66 
6,600 
7,260 
5% 
0.62 
0.61 
3,300 
3,640 
5% 
0.65 
0.64 
4,100 
4,520 
5% 
0.67 
0.67 
4,300 
4,740 
Note: Between cluster ICC = 0.028; Between cluster variance* = 0.095; Between period variance = 0; Number of 
clusters = 10; Number of periods = 2; Alpha = 0.05 
 
5.2 Statistical Methods 
5.2.1 Analysis Plan Overview 
A detailed statistical analysis plan will be published prior to the completion of the trial.  The 
following analysis plan will be conducted independently for the open and closed fracture 
populations. For each population, the analyses and reporting of the results will follow the 
CONSORT guidelines for reporting of both pragmatic trials47 and cluster-randomized trials.48 The 
process of participant enrollment and flow throughout the study will be summarized using a flow-
diagram. Participant demographics and baseline outcome variables will be summarized using 
descriptive summary measures expressed as mean (standard deviation) or median (interquartile 
range) for continuous variables depending on the distribution, and number (percent) for categorical 
variables.49 An ITT principle will be adopted to analyze all outcomes and the unit of analysis will 
be the individual participants. Missing data will be assumed to be missing at random and will be 
handled with multiple imputation.50,51 
 
The primary analysis will compare the treatment groups using the SSI outcome and the secondary 
analysis will compare the unplanned fracture-related reoperation outcome. The secondary 
comparison will be conducted in accordance with best practice guidelines for secondary analyses. 
For all models, the results will be expressed as relative measure of effect (odds, risk, or hazard 
ratios) and corresponding two-sided 95% confidence intervals.  
   

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5.2.2 Analysis of the Study Outcomes 
Adopting an ITT principle, multilevel regression models will be used. Correlation structures will 
be fit based on the observed between cluster and between period effects. A robust sandwich 
estimator will be used to analyze the primary and secondary outcomes. 
 
For the primary outcome, SSI will be the dependent variable and the antiseptic solution (treatment 
group) will be the independent variable. For the secondary outcome, unplanned fracture-related 
reoperation will be the dependent variable and the antiseptic solution (treatment group) will be the 
independent variable. For both analyses, multiple imputation will be used to handle missing data.51  
 
As the optimal methods for analyzing cluster crossover trials continue to evolve, the final statistical 
modeling technique to be used will be determined in accordance with contemporary best practices 
prior to the completion of participant follow-up. A separate Statistical Analysis Plan will be 
developed prior to study closeout. Table 7 below shows a summary of the study outcomes, 
corresponding hypotheses, and currently proposed methods of analysis.   
 
Table 7: Summary of Outcome Analysis Plan 
Objective 
Outcome 
Hypothesis 
Method of 
Analysis 
Name 
Type 
To determine the effect of iodine-based versus 
CHG-based pre-operative antiseptic skin solutions 
on the incidence of SSI and unplanned fracture-
related reoperation. 
SSI 
Binary 
Iodine 
solution will 
be more 
effective than 
CHG solution 
Multi-level 
regression 
model 
Unplanned 
Fracture-
Related 
Reoperation 
Binary 
Iodine 
solution will 
be more 
effective than 
CHG solution 
 Multi-level 
regression 
model 
Note: CHG = chlorhexidine gluconate; SSI = Surgical Site Infection 
 
5.2.3 Subgroup Analyses 
A limited number of a priori subgroup analyses will be performed. The open fracture subgroups 
will include: i) severity of open fracture wound (Gustilo-Anderson type I or II versus III);1 ii) upper 
extremity versus lower extremity open fractures; iii) none, minimal, or surface contamination 
versus contamination embedded in bone or deep soft tissues;34 and, iv) presence or absence of 
comorbidities that affect wound healing. 
 
The closed fracture subgroups of interest include: i) severe soft tissue injury (Tscherne Grade 3 
versus Tscherne Grade 0-2) and, ii) presence or absence of comorbidities that affect wound 
healing. These analyses will be performed by comparing the effect estimates in both groups 
(interaction effect). We hypothesize that effect will differ by subgroup. These analyses will be 
approached and reported in accordance with best practices and guidelines for subgroup 
analyses.33,52–54 Table 8 below shows a summary of the subgroup analysis objectives, 
corresponding outcomes, hypotheses, and methods of analysis for each fracture population. 
 
Table 8: Summary of Subgroup Analysis Plan 
Objective 
Outcome 
Hypothesis 
Method of 
Analysis 
Name 
Type 
Open Fracture Subgroup Analyses 

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Objective 
Outcome 
Hypothesis 
Method of 
Analysis 
Name 
Type 
Severity of open fracture 
(Gustilo-Anderson Type I 
or II vs. Type III) 
SSI /  
Unplanned 
Fracture-
Related 
Reoperation 
Binary 
Iodine solution will be associated 
with a larger reduction in odds for 
SSI and reoperation than CHG 
solution in more severe fractures 
Interaction of 
treatment by 
subgroup 
Upper extremity vs. lower 
extremity fractures 
SSI /  
Unplanned 
Fracture-
Related 
Reoperation 
Binary 
Iodine solution will be associated 
with a larger reduction in odds for 
SSI and reoperation than CHG 
solution in lower extremity 
compared to upper extremity 
fractures 
Interaction of 
treatment by 
subgroup 
None, minimal, or surface 
wound contamination vs. 
embedded wound 
contamination 
SSI /  
Unplanned 
Fracture-
Related 
Reoperation 
Binary 
Iodine solution will be associated 
with a larger reduction in odds for 
SSI and reoperation than CHG 
solution in embedded contaminated 
wounds compared to wounds with 
no, minimal or surface 
contamination  
Interaction of 
treatment by 
subgroup 
Presence or absence of 
comorbidities that affect 
wound healing 
SSI /  
Unplanned 
Fracture-
Related 
Reoperation 
Binary 
Iodine solution will be associated 
with a larger reduction in odds for 
SSI and reoperation than CHG 
solution in participants who have 
comorbidities that affect wound 
healing 
Interaction of 
treatment by 
subgroup 
Closed Fracture Subgroup Analyses 
Severe soft tissue injuries 
(Tscherne Grade 3 vs. 
Tscherne Grade 0-2) 
SSI /  
Unplanned 
Fracture-
Related 
Reoperation 
Binary 
Iodine solution will be associated 
with a larger reduction in odds for 
SSI and reoperation than CHG 
solution in fractures with severe 
soft tissue injuries  
Interaction of 
treatment by 
subgroup 
Presence or absence of 
comorbidities that affect 
wound healing 
SSI /  
Unplanned 
Fracture-
Related 
Reoperation 
Binary 
Iodine solution will be associated 
with a larger reduction in odds for 
SSI and reoperation than CHG 
solution in participants who have 
comorbidities that affect wound 
healing 
Interaction of 
treatment by 
subgroup 
Note: CHG = chlorhexidine gluconate; SSI = Surgical Site Infection 
 
5.2.4 Sensitivity Analyses 
Assessment of the sensitivity or robustness of the findings to the key assumptions is essential in 
trials. The following sensitivity analyses may be conducted to explore the effects of alternative 
analysis models, alternative missing data approaches, balancing prognostic imbalance, as-treated 
analyses, variability in co-interventions, and alternative definitions of SSI. 
 
1. Using different analysis models: There are several methods for analyzing cluster 
randomized crossover trials.51,55 Therefore, our sensitivity analyses will explore alternative 
multi-level models with different correlation structures for the error.52,55  
 
2. Different methods of handling missing data: There are several methods of handling missing 
data in trials.55 Multiple imputation assumes that the data are missing at random—an 
assumption that is not verifiable in practice. Other imputation methods will be used such 
as worst case scenario to impute missing data and assess the robustness of the results.56 For 

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the worst case scenario analysis, we will assume that a random sample of participants lost 
to follow-up experienced a study event. For this sensitivity analysis, the proportion 
assumed to experience a study event will be equivalent to the upper confidence interval of 
the observed pooled event rate for each study outcome.  
 
3. Adjusted analyses for prognostic imbalance: We will also perform sensitivity analyses that 
assume prognostic imbalance between the two treatment groups based on the following 
key variables known to be risk factors for SSI or reoperation after extremity fracture 
management: soft tissue injury, time from injury to definitive fixation, age, work-related 
injury, and employment status.5 For patients with open fractures, these additional risk 
factors will also be considered: Gustilo fracture type, lower extremity fracture, wound 
contamination, time from injury to first debridement, antiseptic wound dressing in the 
emergency department, method of fixation, and wound closure at initial debridement.5 
Adjusted analyses including the above risk factors and treatment group as independent 
variables will be performed for the SSI and reoperation outcomes.  
 
4. As-treated analyses: The proportion of surgical procedures receiving the incorrect, non-
allocated antiseptic solution will be reported. “As-treated” sensitivity analyses will be 
performed using the solution received as the independent variable.  For participants that 
were treated in a single fracture surgery, they will be analyzed using the antiseptic solution 
received.  For participants who received multiple fracture surgeries, two analyses will be 
performed.  First, the antiseptic solution used in their last surgery prior to a study outcome 
event will define their study treatment.  For the second analysis, the antiseptic solution 
received in the majority of their fracture surgeries will define their study treatment.  
Participants who were treated with multiple fracture management surgeries, but received 
equal exposure to both treatment solutions (e.g., one surgery with CHG and one surgery 
with iodine), will be analyzed within their originally allocated treatment group.   
 
5. Co-intervention variability: Selective censoring of one or more clusters and / or treatment 
periods will be performed to further explore between-cluster and between-period 
variability identified in the primary and secondary outcome comparisons. These analyses 
will be used to explore the robustness of the study conclusions in the context of measured 
practice variations in co-interventions that differ between participating sites and / or evolve 
over the duration of the study recruitment. Results that are sensitive to the removal of a 
cluster(s) and / or period(s) will be reported, along with potential clinical hypotheses that 
are supported by the measured clinical practice variation.   
 
6. Quantitative pooling of open fracture and closed fracture populations: We will 
quantitatively pool the treatment effects from the open and closed fracture populations if 
the direction of the effect is consistent across the two populations. The rationale for this 
sensitivity analysis approach is that a consistent direction of effect in the two populations 
suggests that the populations and mechanism of effect are similar enough to provide a 
clinically useful estimate of treatment effect if applied to all surgically treated fractures.  If 
the direction of the effect is in opposite directions, for example, CHG appears to be more 
effective in closed fractures and iodine povacrylex is more effective in open fractures, then 
no pooling will be performed. This scenario would suggest that the populations and 
heterogeneity of treatment effect is too divergent; therefore, a pooled treatment estimate 

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would not be clinically useful since surgeons will continue to view the choice of antiseptic 
skin solution for open and closed fractures patients as separate treatment decisions. 
 
7. Exploratory SSI definitions: The above analyses will be repeated for the primary 
comparison using the FRI outcome and the CDC definition within 1 year of injury to 
determine if the study conclusions are sensitive to alternative definitions of SSI. 
 
Table 9 below shows a summary of each potential sensitivity analysis objectives, corresponding 
outcomes, hypotheses, and methods of analysis.   
 
Table 9: Summary of Sensitivity Analysis Plan 
 
Objective 
Outcome 
Hypothesis 
Method of Analysis 
Name 
Type 
1 
Different analysis 
models 
SSI / 
Reoperation 
Binary 
Iodine solution 
will be more 
effective than 
CHG solution 
Multi-level regression 
models with different 
correlation structures 
2 
Different missing 
data approach 
SSI / 
Reoperation 
Binary 
Iodine solution 
will be more 
effective than 
CHG solution 
Multi-level regression 
models with missing 
data imputed using 
worst-case scenario 
3 
Baseline prognostic 
imbalance 
SSI / 
Reoperation 
Binary 
Iodine solution 
will be more 
effective than 
CHG solution 
Multi-level regression 
models with 
prognostic variables & 
treatment group 
4 
As-treated analysis 
SSI / 
Reoperation 
Binary 
Iodine solution 
will be more 
effective than 
CHG solution 
Multi-level regression 
models using “as 
treated” treatment 
group 
5 
Co-intervention 
variability 
SSI / 
Reoperation 
Binary 
Cluster- and 
period-
variability is 
related to co-
interventions 
Censoring of cluster(s) 
and/or period(s) with 
differences in co-
interventions  
6 
Quantitative 
pooling 
SSI / 
Reoperation 
Binary 
Iodine solution 
will be more 
effective than 
CHG solution 
in all fracture 
patients 
Meta-analysis with 
fixed effects 
7 
Exploratory 
SSI definitions 
FRI / 
CDC SSI within 1 year 
Binary 
Iodine solution 
will be more 
effective than 
CHG solution 
Multilevel regression 
model 
Note: CHG = chlorhexidine gluconate; SSI = Surgical Site Infection; FRI = fracture-related infection; CDC = Centers 
for Disease Control and Prevention 
 
5.2.5 Interim Analysis 
No formal interim analyses are planned and the trial will not be stopped early for benefit. The Data 
and Safety Monitoring Committee (see Section 7.5.6) will review frequent safety reports and will 
collectively make judgments on the strength of evidence and the absolute magnitude and 
seriousness of any safety signals.57 The Data and Safety Monitoring Committee may make 
recommendations regarding the trial. 

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6.0 DATA MANAGEMENT 
 
6.1 Case Report Forms and Data Transmission 
Clinical sites will be provided with the trial CRFs prior to initiation of enrollment. Research 
personnel at each clinical site will submit the required data, as detailed on the CRFs, to the Methods 
Center using the REDCap Cloud electronic data capture system. Clinical site personnel will 
receive a unique login and password for the REDCap Cloud system and will be able to view and 
modify data for participants recruited at their clinical site.  
 
6.2 Data Integrity 
The REDCap Cloud system uses a variety of mechanisms for checking data at the time of entry 
including skip logic, range checks, and data type checks. Upon receipt of new data, the personnel 
at the Methods Center will query all missing, implausible, or inconsistent data. Clinical site 
personnel will be able to review all open queries in the system and will be required to respond 
promptly.   
 
7.0 ETHICS AND DISSEMINATION 
 
7.1 Research Ethics Approval 
The McMaster University Methods Center and all participating clinical sites will receive REB or 
IRB approval prior to commencing participant enrollment. A central IRB and local IRBs/REBs 
will be used based on clinical site logistics. Prior to local commencement of the study, each clinical 
site will provide the Methods Center with a copy of their ethics approval. 
 
7.2 Consent 
In many cluster randomized comparative effectiveness trials, a waiver of consent is obtained from 
the IRB of Record.  The rationale for the waiver of consent is that all patients will receive 
treatments that are effective and within standards of care, they will receive one of the study 
treatments as part of their routine care regardless of study participation, the data collection is 
minimal and obtained from the patient’s medical records, the trial involves no more than minimal 
risk to the patient, and that the waiver of consent will not adversely affect the rights and welfare 
of the patient. Most of these concepts apply to the current trial, as the PREPARE trial is 
comparative effectiveness research where patients will receive one of the preoperative antiseptic 
skin solutions regardless of their participation in the study. Additionally, patients are never 
included in the decision-making process for the choice of antiseptic preparation solution, and, in 
most situations, they are not even aware of which solution is used.  However, in contrast to many 
cluster randomized crossover trials, PREPARE trial personnel will need to contact participants 
directly to collect baseline and outcome data, as this information cannot be reliably obtained from 
the patients’ medical records.  Therefore, study personnel will obtain informed consent from 
patients prior to data collection.  This consent process will allow study participants to be informed 
about the study rationale and provide consent for ongoing surveillance and data collection.   
 
To increase enrollment and to avoid missing potential study participants, the consent process may 
take place up to 3 weeks post-fracture for open fracture patients and up to 6 weeks post-fracture 
for closed fracture patients.  Consultation during the study design phase with IRB members and 
patient advisors confirmed the acceptability of this flexible approach, where consent may be 
obtained after the intervention. The primary rationale for allowing consent after the intervention is 

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consistent with the waiver of consent principles outlined above, but in addition, the patient and 
IRB stakeholders recognized that obtaining consent prior to the patient’s first surgery could add 
undue decision making stress to a patient who is awaiting surgical management of a serious 
extremity injury; allowing consent after their surgery would likely facilitate an improved consent 
process.  
 
The consent process will typically take place in the patient’s hospital room or in the outpatient 
fracture clinic, either before or after the patient has had surgery(ies) to manage their fracture. If 
the patient is unable to provide informed consent (e.g., due to their injury, language restrictions) 
within 3 weeks of their open fracture or 6 weeks of their closed fracture, informed consent will be 
obtained from their proxy. In addition, if a patient has been discharged from hospital prior to being 
invited to participate in the study, a delegated member of the clinical care team may initiate the 
consent process by telephone, as approved by the IRB of Record.   
 
To obtain informed consent, delegated study personnel should follow the below procedures: 
• Present study information in a manner that is understandable to the potential 
participant/proxy. 
• Discuss the study with the potential participant/proxy and answer any questions he or she 
asks. 
• Allow the potential participant/proxy an opportunity to discuss participation with their 
family, friends, or family physician, if desired.  
• Confirm that the participant/proxy understands the risks and benefits of participating in the 
study and that their participation is voluntary. 
• Complete and obtain signatures for informed consent form and obtain contact information 
from the participant/proxy. 
• Provide/send the participant/proxy with a paper/electronic copy of the signed consent form. 
 
Consent may be obtained electronically or using pen and paper consent forms, as approved by the 
IRB of Record.  If potential participants are contacted by telephone, documenting written informed 
consent will involve the following procedures: 
• The study team confirms the potential participant’s interest in learning more about the 
study and verifies the mailing address or fax number to which the consent form can be sent. 
• A blank consent form is mailed or faxed along with a cover letter that introduces the study 
and explains when the phone conversation will occur. A stamped, self-addressed envelope 
is provided if standard mail is used so the participant can return the signed consent 
document to the study team. 
• After the potential participant has received the document, a member of the study team calls 
the participant and walks through the entire document over the phone, answering questions 
and making notes about the participant’s questions. Time and date of the conversation 
should be recorded. 
• Once all questions are answered, the participant signs the consent form if they are willing 
to participate. S/he returns the consent form by mail or fax. 
• Once received, the study team member who conducted the consent conversation should 
sign the consent form and date with today’s date. To explain the discrepancy, this 
individual should also write a note on the consent form stating that the participant’s consent 
was obtained by phone on xx date (the date the participant signed.) 

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• The participant should receive back a fully-signed copy of the consent form for their 
records. 
 
The process of obtaining and documenting informed consent will be completed in accordance with 
local Good Clinical Practice recommendations. Consent procedures and forms, and the 
communication, transmission and storage of patient data will comply with the IRB of Record 
requirements for compliance with The Health Insurance Portability and Accountability Act.  
 
Upon providing informed consent, study participants will be followed for 12 months from their 
fracture. Given the short follow-up time, the need for a regular reassessment of consent will not 
apply; however, participants may withdraw their consent at any time.  
 
7.3 Confidentiality 
Information about study participants will be kept confidential and will be managed in accordance 
with the below rules: 
• All study-related information will be stored securely. 
• All study participant information will be stored in locked file cabinets, or locked room, 
as applicable, and accessible only to study personnel. 
• All paper and electronic CRFs will be identified only by a coded participant number. 
• All databases will be password protected. 
 
In the event that a participant revokes authorization to collect or use personal health information, 
the clinical site retains the ability to use all information collected prior to the revocation of 
participant authorization. For participants who have revoked authorization to collect or use 
personal health information, attempts should be made to obtain permission to collect at least vital 
status (i.e., primary outcome data) at the end of their scheduled study period. 
 
7.4 Protocol Amendments 
Any amendments to the study protocol which will affect the conduct of the study, impact the safety 
or benefits to participants or affect the analysis and the interpretation of the safety and efficacy of 
the intervention under investigation (e.g., changes to the study objectives, study design, sample 
size, or study procedures) will necessitate a formal amendment to the protocol. Any protocol 
amendments will be approved by the Principal Investigators and will require approval by the 
McMaster University REB, the Central IRB, local IRBs/REBs, as well as the Funder (as needed). 
The Methods Center will also file an amendment to all applicable regulatory agencies for changes 
to the protocol made after the original regulatory approval.  Clinical sites will also be required to 
submit amendment requests to their IRB of Record to obtain approval for the amendment and to 
provide the Methods Center with a copy of this approval. Administrative changes (e.g., minor 
corrections or clarifications that have no effect on the way the study is conducted) will not need to 
undergo a formal amendment process. 
 
7.5 Adverse Event Reporting and Definitions 
7.5.1 Serious Adverse Event (SAE) 
A SAE is any adverse event that is any of the following: 
• Fatal 
• Life threatening 
• Requires or prolongs hospital stay 

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• Results in persistent or significant disability or incapacity 
• A congenital anomaly or birth defect 
• An important medical event  
 
7.5.2 Unanticipated Problems Resulting in Risk to Participant or Others 
Any incident, experience, or outcome that meets the following criteria: 
• Unexpected in nature, severity, or frequency (e.g., not described in study-related 
documents such as the ethics-approved protocol or consent form, etc.). 
• Related or possibly related to participation in the research (i.e., possibly related means 
there is reasonable possibility that the incident experience or outcome may have been 
caused by the procedures involved in the research). 
• Suggests that the research places participants or others at greater risk of harm (including 
physical, psychological, economic, or social harm).  
 
7.5.3 Serious Unexpected Adverse Drug Reactions  
A serious adverse drug reaction means a noxious and unintended response to a drug that occurs at 
any dose and that requires in-patient hospitalization or prolongation of existing hospitalization, 
causes congenital malformation, results in persistent or significant disability or incapacity, is life-
threatening or results in death.  An adverse drug reaction is considered unexpected when its nature 
(i.e., specificity or outcome), severity or frequency is either not identified, or is not consistent with 
the term or description used in the product labelling. 
 
7.5.4 Adverse Event Reporting 
Clinical sites are responsible for reporting SAEs and serious unexpected adverse drug reactions 
immediately to the Methods Center via the REDCap Cloud system. Significant new information 
on ongoing SAEs should also be provided promptly to the Methods Center via the REDCap Cloud 
system. Unanticipated problems resulting in risk to participants or others are also to be reported 
promptly to the Methods Center. 
 
The Methods Center will inform all applicable regulatory agencies of any serious unexpected 
adverse drug reaction in respect of the drug that has occurred as follows: 
(a) if it is neither fatal nor life threatening, within 15 days after becoming aware of the information; 
and 
(b) if it is fatal or life threatening, within seven days after becoming aware of the information. 
Within eight days after having informed the regulatory agency of any serious unexpected adverse 
drug reactions, the Methods Center will submit to the regulatory agency a complete report in 
respect of that information that includes an assessment of the importance and implication of any 
findings made. 
Adverse drug reactions that are expected or unexpected, but not serious, will not be reported to the 
regulatory agency, but rather monitored and tracked by the Methods Center. The Methods Center 
will report to applicable regulatory agencies "expected, serious" adverse drug reactions, where an 
increase in the rate of occurrence or severity, was judged to be clinically important. 
 
A causality assessment will be undertaken by the Methods Center, together with the responsible 
investigator for clinical investigation cases, and any case judged as having a reasonable suspected 
causal relationship to the medicinal product will be reported.  

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7.5.5 Clinical Site Reporting – IRB and REB 
Clinical sites are responsible for reporting SAEs and unanticipated problems resulting in risk to 
participants or others to their local REB/IRB or the Central IRB in accordance with local reporting 
requirements. Copies of each report and documentation of ethic board notification and receipt will 
be kept in the clinical site’s study file. 
 
7.5.6 Data and Safety Monitoring Committee 
As per the FDA guidance document the Establishment and Operation of Clinical Trial Data 
Monitoring Committees for Clinical Trial Sponsors, a Data and Safety Monitoring Committee will 
oversee the safety of the trial participants and the overall conduct of the trial. The members of the 
Data and Safety Monitoring Committee will include two orthopaedic surgeons, an infectious 
disease expert, a biostatistician and a fracture patient representative. One orthopaedic surgeon will 
act as the Chair of the Committee. The Data and Safety Monitoring Committee will be responsible 
for safeguarding the interests of study participants, assessing the safety and efficacy of study 
procedures, and for monitoring the overall conduct of the study. The Data and Safety Monitoring 
Committee will frequently review enrollment and demographic summaries, listings of protocol 
deviations, and summaries and listings of SAEs. They will advise the Principal Investigators and 
study team on any concerns related to participant safety and trial conduct, and will make 
recommendations for the study to continue as designed, for study termination, for study 
continuation with major or minor modifications, or temporary suspension of enrollment until some 
uncertainty is resolved. We will develop a Data and Safety Monitoring Committee charter to guide 
the process. 
 
7.6 Dissemination Policy 
The results from each fracture population will be submitted for publication regardless of whether 
there are significant findings. Every attempt will be made to ensure that the amount of time 
between completion of data collection and release of study findings are minimized. 
 
8.0 SUB-STUDY: PATIENT EXPERIENCES IN THE AQUEOUS-PREP AND PREPARE 
TRIALS  
 
8.1 Introduction 
Patient and stakeholder involvement in the design of randomized controlled trials is increasingly 
becoming recognized as an essential component of a trial’s success.58,59  Patient and stakeholder 
involvement (PSI) has been seen as the paradigm shift from research being done “to” or “for” 
patients, to research being performed “with” or “by” patients themselves.60  PSI allows for 
democratization of the research process and empowering patients throughout the entire research 
process – from design through to knowledge dissemination.61  Research has found that patients 
and stakeholders are motivated to be involved in research for a wide variety of reasons, including 
a desire to contribute to research for the benefit of others.62  
 
Prior research has argued that PSI enhances the focus of clinical trials on outcomes that are relevant 
to patients themselves, thus increasing the utility of any research findings.63  Furthermore, PSI has 
been argued to improve recruitment and retention rates, while raising the quality of research 
findings and ultimately helping with the dissemination of research findings.64  Lastly, PSI may be 
able to improve patient safety when patients are involved in safety reporting in hospital settings.65  
 

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Despite these findings, a recent systematic review estimates that far less than 1% of clinical trials 
engage patients in any meaningful or active way.66  From the onset of the PREP-IT trials (i.e. the 
Aqueous-PREP and PREPARE trials), the PREP-IT investigators have engaged multiple patient-
partners and stakeholders in the design, conduct, and implementation of the PREP-IT trials.  One 
of our engagement goals is to identify ways in which we can better engage with PREP-IT study 
participants.  To support this goal, we seek to learn about PREP-IT participants’ experiences within 
the PREP-IT trials.  This knowledge will be used to improve the study team’s ability to engage 
study participants and provide study information in a meaningful and accessible manner.  
Additionally, the unique design of the PREP-IT trials (e.g., consent after the intervention, minimal 
follow-up, minimal requirements for participants) provides a novel trial to investigate this 
question.  This led to the current sub-study. 
 
8.2 Rationale and Objectives 
One of the mandates of the PREP-IT program is to improve orthopaedic fracture research through 
meaningful engagement with our patient-partners and stakeholders.  The objective of this sub-
study is to learn about PREP-IT participants’ experiences with participating in the Aqueous-PREP 
or PREPARE trial.  The results of this sub-study will be used to develop strategies to better engage 
research participants both in the PREP-IT trials as well as in future clinical trials.  
 
8.3 Sub-Study Design 
This sub-study will consist of an exit survey that will be given to a subset of participants in the 
PREP-IT trials.  Select clinical sites participating in the Aqueous-PREP and / or PREPARE trial 
will be invited to participate in the sub-study.   
 
The exit survey is comprised of 14 questions that includes multiple choice and brief open-ended 
questions.  All of the questions use clear and simple language written at or below a grade eight 
reading level to enhance the validity of results.  The survey length has been kept to a minimum to 
maximize response rate and limit barriers that would affect its proper completion.   
 
The survey was created after reviewing the current literature and with input from the PREP-IT 
investigators, research coordinators, patient-partners, and stakeholders.  Engaging the larger study 
team follows the PREP-IT philosophy of meaningful engagement, as well as helps to ensure that 
no vital questions were missed and that the survey wording is clear and easily understandable to 
the target audience.  The questionnaire was pre-tested on a sample of convenience.  
 
8.4 Survey Participants and Distribution 
All potential substudy participants, or their proxies, will be required to provide informed consent 
specifically for the substudy prior to completing the survey.  Informed consent for the substudy 
may be obtained at the time of enrollment in the Aqueous-PREP or PREPARE trial using 
procedures described in sections 4.3.1 and 7.2, or in-person at a subsequent follow-up visit or time 
of survey administration using a pen and paper consent form.  The patient or proxy must be 
provided with a copy of the signed informed consent form. All sites within the United States of 
America must conduct their consenting process in accordance with HIPAA (Health Insurance 
Portability and Accountability Act) regulations as approved by their institutions, and sites in 
Canada must comply with the Personal Information Protection and Electronic Documents Act 
(PIPEDA). 
 

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Clinical sites participating in the sub-study will offer the survey to all eligible participants at the 
time they complete their one-year follow up visit. The survey will be sent to participants either 
through mail, email or RedCap Cloud, given to them on paper at a follow-up visit, or administered 
over the phone, depending on each individual participant’s preference.  The Research Coordinator 
may also telephone or text the participant to remind them to complete the exit survey.  We will 
document the number of participants invited to participate in the survey as well as the number of 
participants who decline participation. 
 
8.5 Data Entry 
The exit survey responses will be entered into the Aqueous-PREP / PREPARE trial’s electronic 
data capture (EDC) system. 
 
8.6 Sample Size 
Sample size was calculated using a 5% margin of error, with 95% confidence intervals, a potential 
population of all patients who have completed one year follow up (approximately 1600 patients) 
and an expected response rate of 50%.  With this in mind, a sample size of approximately 310 
patients who complete every survey question will be required.67  As such, the survey will be 
distributed to all participants at participating clinical sites until our sample size of at least 310 
participants is achieved.     
 
8.7 Data Analysis 
We will summarize all variables with frequencies and percentages.  The short form questions will 
be coded appropriately based on themes.   
 
8.8 Anticipated Implications of Results 
This research serves as an important step towards understanding patients’ perspectives as 
participants in a clinical trial.  Additionally, the research may influence how future clinical trials 
are designed and conducted, with the overall goal of a greater focus on the patient experience and 
increasing patient involvement in research.  Lastly, the results of this sub-study could help the 
study team to develop aids (e.g., posters, pamphlets, etc.) to improve patients’ understanding of 
clinical research and overall experience with the PREP-IT trials. 
 
9.0 SUB-STUDY: THE IMPACT OF HETEROTOPIC OSSIFICATION PROPHYLAXIS 
AFTER SURGICAL FIXATION OF ACETABULAR FRACTURES: NATIONAL 
TREATMENT PATTERNS AND RELATED OUTCOMES  
 
9.1 Introduction 
Heterotopic ossification (HO) is a common complication after surgical fixation of acetabular 
fractures, with incidence rates reported as high as 90%.68–71  HO can be a debilitating complication 
and surgical excision for more severe cases carries a high complication rate.72  Numerous strategies 
have been employed to prevent HO formation but results are mixed and the optimal treatment 
strategy remains controversial. 
 
The most common modalities used to prevent HO formation are oral administration of 
indomethacin or single-dose external beam irradiation therapy (XRT).68,73–77  Despite the common 
use of indomethacin and observational data to support its use,76,77 more recent randomized 
controlled trials (RCTs) have failed to demonstrate any significant reduction in the incidence of 
severe HO when patients were administered indomethacin versus placebo.78,79  Similarly, XRT has 

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been shown to be effective against HO formation in smaller observational studies, but there are no 
adequately powered RCTs to support its use compared to placebo.68,75  Additionally, there remain 
concerns with the use of XRT as it relates to cost (over 200 times that of indomethacin), risk of 
radiation-induced sarcoma, and increased rates of non-infectious wound healing problems.80–83  
 
9.2 Rationale and Objectives 
Given the high incidence, impact on outcomes, and controversy regarding treatment, there remains 
a need for continued research to determine optimal treatment strategies for HO prophylaxis after 
posterior acetabular surgery. The PREPARE trial cohort is an ideal opportunity to evaluate 
variations in practice treatment patterns across a wide range of clinical sites. The primary objective 
of this sub-study is to describe national HO prophylaxis treatment patterns after posterior 
acetabular fracture surgery. Secondarily, we will determine the association between treatment 
modalities – indomethacin, XRT, or no prophylaxis – and the prevalence of HO formation after 
acetabular fracture surgery. 
 
9.3 Sub-Study Design 
This sub-study will include a subset of participants in the PREPARE trial.  All clinical sites 
participating in the PREPARE trial that enrolled patients with closed AO-type 62 fractures will be 
invited to participate in the sub-study.   
 
From the participant’s medical record, we will obtain data related to the injury characteristics of 
the fracture, the surgical approach at time of fixation, and any notable HO present on follow-up 
radiographs. HO on follow-up radiographs will be measured and classified as described by 
Brooker et al.84  These data fields were selected after reviewing the current literature and with 
input from the PREPARE investigators.  A virtual meeting was held to engage participating sites 
and ensure that no vital questions were missed and that the language is clear and easily 
understandable.   
 
All potential sub-study participating clinical centers will be identified by their enrollment of 
patients with closed AO-type 62 acetabular fractures. The CRF will be distributed to all sites with 
eligible participants.  
 
9.4 Data Entry 
The CRF responses will be entered into the PREPARE trial’s electronic data capture (EDC) 
system. 
 
9.5 Sample Size 
A statistical power analysis was performed for sample size estimation based on previous data.75 
With an alpha = 0.05, power = 0.80, and allocation ratio of 1, the projected total sample size needed 
to detect between group differences was 58 patients with Brooker III/IV as an endpoint and 156 
patients with Brooker IV as an endpoint.85 
 
9.6 Data Analysis 
We will summarize all variables with frequencies and percentages. Multivariable regression 
analyses will be performed to evaluate the association of HO formation by HO prophylaxis 
modality. These models will be stratified by fracture classification and adjusted for predictors of 
HO formation including Injury Severity Score (ISS). 
 

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9.7 Anticipated Implications of Results 
We hypothesize that despite the limited evidence to support the use of indomethacin as an effective 
HO prophylaxis strategy, many centers still utilize this treatment protocol. We also anticipate to 
find that HO prevention strategies such as XRT and indomethacin are not associated with the 
severity of HO formation as compared to a no prophylaxis control group. 
 
To our knowledge, this study will be the largest of its kind and will also be the first to reveal HO 
prophylaxis patterns on a national level. These data will both help inform the orthopaedic trauma 
community on best practices and potentially decrease the burden of HO formation after posterior 
acetabulum fracture surgery. 
 
10.0 SUB-STUDY: MEASUREMENT OF TROPONIN FOLLOWING FRACTURE 
REPAIR SURGERY 
 
10.1 Introduction 
Myocardial injury after noncardiac surgery (MINS) is defined as an acute elevation of troponin 
due to myocardial ischemia occurring during or within 30 days after noncardiac surgery. 
Diagnostic criteria for MINS include patients that fulfill the Universal Definition of Myocardial 
Infarction (MI), and patients with ischemic troponin elevation without any ischemic feature (e.g., 
chest pain or ischemic electrocardiographic findings).86,87 Specifically, MINS is defined as a 
postoperative peak level of non-high-sensitivity troponin T (TnT) of 0.03 ng/mL or greater,87 or a 
postoperative peak of high-sensitivity troponin T (hsTnT) of 20 to <65 ng/L with an absolute 
change of ≥5 ng/L or a postoperative peak of hsTnT ≥65 ng/L with no evidence of a non-ischemic 
etiology (such as rapid atrial fibrillation, sepsis, or pulmonary embolism).86,88,89 Those thresholds 
were determined to be independently associated with death at 30 days. A high-sensitivity troponin 
I (hsTnI) ≥60 ng/L (ARCHITECT STAT Abbot assay),88 and a hsTnI ≥75 ng/L (Siemens 
Healthineers ADVIA Centaur Assay)89 are also associated with major cardiovascular events 30 
days after noncardiac surgery, and are suggested as thresholds for MINS. For other troponin 
assays, physicians should consider any elevation above the 99th percentile upper reference limit.86 
 
Recent research has found that MINS is common in certain patients undergoing orthopaedic 
surgery. The VISION orthopaedic sub-study, a large prospective cohort study, identified that 
among patients ≥45 years of age who had orthopaedic surgery 11.9% (367/3092) had MINS.90  
This study also demonstrated that MINS was independently associated with 30-day mortality in 
this population. Specifically, orthopaedic patients without and with MINS had a 30-day mortality 
rate of 1.0% and 9.8%, respectively (odds ratio [OR], 11.28; 95% confidence interval [CI], 6.72 
to 18.92). Importantly, the 30-day mortality rate was increased for patients with MINS who had 
an ischemic feature (i.e., symptoms, or evidence of ischemia on electrocardiography or imaging) 
(OR, 18.25; 95% CI, 10.06 to 33.10) and for those who did not have an ischemic feature (OR, 
7.35; 95% CI, 3.37 to 16.01). The proportion of orthopaedic patients with MINS who were 
asymptomatic and in whom the myocardial injury would have probably gone undetected without 
serum troponin monitoring was 81.3% (95% CI, 76.3% to 85.4%).    
 
Based on these recent findings (Thomas, JBJS 2020)90, there is a strong rational for routine 
perioperative screening of troponin levels in fracture surgery patients. Supporting those results, 
the Canadian Cardiovascular Society (CCS) Guidelines,91 the European Society of Cardiology 
(ESC)92 and the most recent Universal definition of MI statement86 also recommend that higher 
risk patients undergoing noncardiac surgery should be routinely monitored for MINS. 

Page 45 of 53 
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10.2 Rationale and Objectives 
It remains unknown if standard perioperative troponin monitoring is incorporated in routine 
clinical practice in fracture patients requiring surgical management. Thus, the prevalence of MINS, 
and its associated mortality, is unknown in this population. The VISION orthopaedic study 
primarily included patients undergoing elective orthopaedic procedures (e.g. hip and knee 
replacements).  Fracture patients may be at higher risk, considering they undergo urgent surgery. 
The VISION study demonstrated that urgent and emergent surgeries are associated with higher 
mortality than elective surgeries.88 Moreover, the HIP ATTACK trial demonstrated that 
myocardial injury after randomization happened in 901/2970 (30.3%) hip fracture patients with 
routine postoperative troponin screening performed.93 There is biological plausibility and evidence 
from large cohort studies94 to support that fracture patients have higher incidence of postoperative 
adverse outcomes, including MINS, as the physiologic stress of the fracture (e.g., inflammation, 
bleeding, catecholamine release) may contribute to clinical complications such as an acute 
myocardial injury.  
 
Therefore, the objective of this sub-study is to determine the proportion of PREPARE participants 
≥45 years of age who have perioperative troponin levels measured as part of their standard of care.   
 
10.3 Sub-Study Design 
All clinical sites participating in the PREPARE trial will be invited to participate in the sub-study 
This sub-study will include a subset of participants in the PREPARE trial: 1) participants enrolled 
after 1-February-2020 and 2) participants ≥45 years of age. 
 
Study personnel will document the following in the case report forms: 
1. Whether any serum troponin levels were ordered between the perioperative window of 
hospital admission to postoperative day 3, inclusive. 
2. All dates, times, and serum troponin concentration levels, troponin type (e.g., TnT, 
hsTnT, hsTnI) and assay used, and upper reference limit, during the perioperative 
window of interest. 
3. Evidence of ischemic etiology associated with elevated troponin results. 
 
10.4 Data Entry 
The CRF responses will be entered into the PREPARE trial’s electronic data capture (EDC) 
system. 
 
10.4 Sample Size 
We anticipate that data from 1,000 PREPARE participants will be included this sub-study.  Sample 
size will be driven by the number of sites willing to participate in this sub-study, as well as the 
number of patients enrolled before enrollment for the parent PREPARE trial closes.  Assuming 
the incidence of measuring serum troponin levels is 10% among study participants, a sample size 
of 1,000 patients will ensure the precision of this estimate is within 2% (95% confidence interval 
8%-12%). 
 
10.5 Data Analysis 
A sub-study specific statistical analysis plan will be developed prior to data analysis.  All analyses 
are intended to be explanatory and will be primarily descriptive. 
 

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10.6 Anticipated Implications of the Results 
The results of this sub-study will inform the potential plans for a large, definitive cohort study.  
The objectives of this large cohort study will be: 1) To determine the incidence of MINS in 
surgically managed fracture patients; 2) To explore the practice variability with the treatment 
management of patients diagnosed with MINS; and, 3) To compare the mortality rate between 
patients with MINS and those without MINS.  This large cohort study will provide orthopaedic 
trauma surgeons with an accurate estimate of MINS and its associated mortality in the fracture 
patient population. It will also help to guide policy decisions regarding the utility of routinely 
screening troponin levels in the fracture surgery population.  This sub-study is the important first 
step in planning for this larger cohort study.  
 
 
 
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