Effectiveness of Iodophor vs Chlorhexidine Solutions for Surgical Site Infections and Unplanned Reoperations for Patients Who Underwent Fracture Repair

Key Points Question What is the effectiveness of surgical skin preparation with iodophor solutions vs chlorhexidine solutions at reducing 90-day surgical site infections and unplanned fracture-related reoperations within 1 year of injury? Findings This trial master protocol describes 2 multicenter pragmatic cluster randomized crossover trials, Aqueous-PREP (Pragmatic Randomized Trial Evaluating Pre-Operative Aqueous and Antiseptic Skin Solution in Open Fractures) and PREPARE (Pragmatic Randomized Trial Evaluating Pre-Operative Alcohol Skin Solutions in Fractured Extremities), which seek to compare the effectiveness of iodophor and chlorhexidine surgical skin preparation solutions at reducing surgical site infections and unplanned fracture-related reoperations. Meaning Because prophylactic skin antisepsis is used prior to all surgical procedures and the application, cost, and availability of all study solutions are similar, the results are poised to inform clinical guidelines and bring about change in clinical practice.


Background
The prevention of infection is an important goal influencing perioperative 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 Version: 2.1 04-Nov-2019 tissue injury (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. Version: 2.1 04-Nov-2019 124 125

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. 126  127 1

.1 Extremity Fractures and Surgical Site Infections 128
More than one million Americans suffer an extremity fracture (broken bone in the arm, leg, or 129 pelvis) that requires surgery each year. 2,3 Approximately 5% (or 50,000) of surgical fracture 130 patients develop a surgical site infection (SSI), 4,5 which is twice the rate among most surgical 131 patients and nearly five times the rate among patients undergoing elective orthopaedic surgeries 132 (e.g., joint replacement). 6 Patients who develop a SSI after their fracture fixation surgery 133 experience a long and difficult treatment pathway. Researchers have identified that when a 134 fracture patient experiences a SSI, they typically undergo at least two additional surgeries to 135 control the infection, spend a median of 14 additional days in the hospital, and have significantly 136 lower health related quality of life (HRQL). 7 Similarly, results from the recently completed Fluid 137 Lavage of Open Wounds (FLOW) trial confirmed that patients who had a SSI, or another 138 complication, that required an additional surgery reported significantly lower physical and 139 mental HRQL in the 12 months following their fracture compared to patients who did not 140 experience a SSI. 8  and emergent cases. In the first period, patients received 7.5% povidone-iodine scrub, 70% 202 isopropyl alcohol scrub, and 10% povidone-iodine skin paint. The second group received 2% 203 CHG in 70% isopropyl alcohol (CHG group), and the third group received 0.7% iodine 204 povacrylex in 74% isopropyl alcohol. Adjusted comparisons were performed using the intention-205 to-treat (ITT) principle and an as-treated analysis. Lower SSI rates were seen in the povidone-206 iodine skin paint group (4.8%) and the iodine povacrylex in isopropyl alcohol group (4.8%), 207 compared with the SSI rates in the 2% CHG in 70% isopropyl alcohol group (8.2%) (P< 0.05; 208 povidone-iodine skin paint odds ratio: 0.56, 95% CI: 0.40-0.79). 21 While the results of the 209 Swenson study contradict those of the smaller randomized controlled trials, this large pragmatic 210 study further highlights that the choice of antiseptic skin solution affects SSIs, and data to select 211 the best solution remain conflicting.

213
Considering the conflicting data, the most recent Cochrane systematic review comparing the 214 efficacy of pre-operative antiseptic skin solutions for clean surgery concluded, "investment in at 215 least one large trial (in terms of participants) is warranted to add definitive and hopefully 216 conclusive data to the current evidence base. Ideally any future trial would evaluate the iodine-217 containing and CHG-containing solutions relevant to current practice…" 24  There are several chemical properties to suggest iodine povacrylex may be more effective than 278 CHG at preventing extremity fracture SSI. 23 Firstly, iodine has a potentially broader spectrum of 279 antimicrobial activity. 23 Secondly, many open fracture patients require repeat surgical 280 debridement, and therefore, these patients will receive multiple exposures to the pre-operative 281 antiseptic solution. Extended use of iodophors has not been associated with the selection of 282 resistant bacterial strains, whereas bacterial resistance to CHG has been documented. 23 from the FLOW trial suggest that 58% of the reoperation events were caused by fracture 298 nonunion or a hardware failure related to an infection, wound-healing problem, or bone-healing 299 problem (n= 188/323). This is consistent with the data presented in Figure 1, confirming a high 300 proportion of fracture infections requiring surgery occurred beyond the 90-day surveillance 301 period for SSI. 18 Therefore, given the rationale that iodophors may be more effective in 302 preventing SSI, it is clinically plausible that its use may also reduce unplanned fracture-related 303 reoperations

Study Objectives and Hypotheses 330
The overarching objective of this trial is to compare the effectiveness of iodine povacrylex (0.7% 331 free iodine) in 74% isopropyl alcohol versus 2% CHG in 70% isopropyl alcohol for the 332 management of extremity fractures that require surgical treatment. Open and closed fracture 333 participants will be recruited separately to compare the independent effectiveness of the study 334 solutions in each population. SSI will be the primary outcome for comparing effectiveness 335 (primary objective), and unplanned fracture-related reoperation will be the secondary outcome 336 for comparison (secondary objective The PREPARE trial will also explore the possibility of differential treatment effects of the pre-360 operative antiseptic skin solutions among clinically important subgroups within each 361 independent fracture population. The closed fracture subgroups will be defined by: i) severity of soft tissue injury (Tscherne grade 371 3 versus grades 0-2), and ii) presence or absence of comorbidities that affect wound healing.

373 2.3.3 Subgroup Hypotheses 374
It has been established that several patient and injury factors are frequently associated with worse 375 patient outcomes after extremity fractures. 30,31 As a result, we hypothesize that iodine povacrylex 376 (0.7% free iodine) in 74% isopropyl alcohol will be associated with a larger reduction in odds for 377 SSI and unplanned fracture-related reoperations among patients with a higher risk for extremity 378 fracture SSI. Specifically, in both the open and closed fracture populations we expect to observe 379 this heterogeneity of treatment effect in patients with more severe soft tissue injury and patients 380 with increased comorbidities due to the potentially broader antimicrobial coverage, stronger 381 tissue adherence, and increased antiseptic longevity of iodine povacrylex. 32 The credibility of all 382 subgroup analyses will be assessed in accordance with criteria outlined by Sun  This study is a multi-center pragmatic cluster randomized crossover trial with two independent 400 populations of surgically treated fracture participants: 1) the open fracture population consisting 401 of a minimum of 1,540 participants with open extremity fractures; and, 2) the closed fracture 402 population of a minimum of 6,280 participants with closed lower extremity or pelvic fractures. 403 The unit of randomization is the orthopaedic practices within clinical sites (clusters), with 404 individual patients being the unit of analysis. The procedures for enrollment, study interventions, 405 follow-up, and analyses within the open and closed fracture populations will follow the same 406 protocol (with noted differences as applicable). Recruitment for each treatment group will be 407 performed in multiple iterations of approximately two-month periods. Each orthopaedic practice 408 will initially be randomized to use one of two pre-operative surgical skin preparation solutions 409 (iodine povacrylex (0.7% free iodine) in 74% isopropyl alcohol versus 2% CHG in 70% 410 isopropyl alcohol) for open and closed extremity fracture surgeries at their institution (Figure 2). 411 Upon completion of the two-month period, each orthopaedic practice will crossover to the 412 alternative treatment allocation and complete another two-month recruitment period. This 413 process of alternating treatment periods (crossovers) will continue until the minimum sample 414 size is achieved for each fracture population and the study's budgeted recruitment duration is 415 completed.

417
Upon completion of recruitment, it is expected that each orthopaedic practice will enroll a 418 minimum of 77 open fracture patients and 314 closed lower extremity or pelvic fracture patients 419 per treatment (a minimum of 154 open fracture patients and 628 closed lower extremity or pelvic 420 fracture patients in total) as applicable, and that most clinical sites will exceed this minimum 421 recruitment goal. Clinical site personnel will screen potential patients for eligibility, and if 422 eligible, they will be invited to participate in the trial. Study participants will be assessed at 423 regular intervals in the one year following their fracture. The primary outcome will include any 424 SSI event from the time of fracture to the end of the 30-and 90-day post-operative periods from 425 their definitive fracture management surgery. The secondary outcome will include unplanned 426 fracture-related reoperations that occur within one-year of their fracture. A blinded Adjudication 427 Committee will review SSIs and unplanned fracture-related reoperations to confirm that they 428 meet the criteria for being a study event.

Pragmatic-Explanatory Continuum 433
In accordance with recommended methodology standards, we have used the PRagmatic-434 Explanatory Continuum Indicator Summary (PRECIS-2) toolkit to evaluate the PREPARE trial 435 design decisions to determine whether these decisions will lead to a study that answers, "Does 436 this intervention work under usual conditions?" (pragmatic) versus "Can this intervention work 437 under ideal conditions?" (explanatory). The PRECIS-2 tool uses a 5-point Likert scale in 9 438 domains to evaluate the continuum of design choices. A domain score of 5 indicates "very 439 pragmatic," while a score of 1 suggests "very explanatory." Table 1 outlines the investigators' 440 assessment of the trial design and the rationale for each assessed score and Figure 3 displays the 441 PRECIS-2 wheel. 442 443 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.
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.  c. For each fracture, the entire injured anatomic region will be included. 34 Therefore, 575 if there are two fractures that anatomically communicate, they will be considered 576 within the same region (e.g., within the shoulder region, forearm, etc. fracture of the appendicular skeleton will be screened for participation within 3 weeks of their 598 fracture. Patients 18 years of age or older who present to a recruiting hospital for surgical 599 treatment of a closed lower extremity or pelvic fracture(s) will be screened for participation 600 within 6 weeks of their fracture. To screen patients for eligibility, designated study personnel at 601 each clinical site will develop a patient enrollment plan. This plan will typically consist of daily 602 participation in orthopaedic patient rounds and a review of daily listings of hospital admissions for 603 patients with open fractures and or closed lower extremity or pelvic fractures. Upon identification, 604 the study personnel will screen the patient for eligibility and if eligible, approach them for informed 605 consent. Study participants with open fractures must be enrolled within 3 weeks of their fracture(s) 606 and study participants with closed fractures must be enrolled within 6 weeks of their fracture(s). 607 Enrollment may take place at any time within this window. If the patient is unable to provide 608 informed consent (e.g., due to their injury) at the time they were initially identified, informed 609 consent may be delayed until they are able to provide informed consent. Alternatively, if the patient 610 is unable to provide informed consent, informed consent may be obtained from their proxy, with 611 consent obtained from the patient when/if the patient is able to provide consent. Allowing informed 612 consent from a patient's proxy healthcare decision maker will reduce the risk of recruitment bias 613 against the most severely injured patients. In addition, potentially eligible patients will be 614 approached to participate in the trial, even if they did not receive the correct pre-operative 615 antiseptic skin solution. This is consistent with the ITT principle and is necessary to maintain the 616 Page 20 of 47 Version: 2.1 04-Nov-2019 prognostic balance achieved during the cluster randomization. All screened patients will be 617 classified as included, excluded, or missed. See Table 2 below for the Schedule of Events. 618 619

623
Visits are to be completed at routine clinic visits. When necessary, visits may also be completed by telephone, text, 624 email, standard mail, and/or a review of the participant's medical record.

625
Follow-up visit windows touch so that participants will always fall into a specific window. Treatment allocation will be determined using a cluster-randomized crossover trial design. The 674 order of treatment allocation for each orthopaedic practice (cluster) will be randomly assigned 675 using a computer-generated randomization table. Each site will start with the initially allocated 676 study solution and crossover to the other solution for their second recruitment period. Both the 677 open fracture and closed lower extremity and pelvic fracture populations will receive the same 678 treatment allocation and follow the same crossover schedule. The process of alternating 679 treatments will repeat approximately every two months as dictated by the initial randomization. 680 For sites that enroll for more than 1 year, the order of treatment allocation may be reversed after 681 12 months to ensure equal distribution of each treatment across each calendar month in the 682 study's duration (Figure 2). Randomization will be completed by personnel at the CEO Methods 683 Center at the onset of the trial. Personnel from the Methods Center will notify personnel at each 684 participating clinical site of their treatment allocation order. This will allow each participating 685 clinical site to begin preparing for the first run-in period. 686 687 4.5 Blinding 688 The orthopaedic team (including the study coordinators) cannot be blinded to the treatment 689 allocation as the antiseptic solutions are visually distinguishable and these individuals need to 690 lead the implementation of the cluster-crossover protocol at their clinical site. The Adjudication 691 Committee Members and data analysts will be blinded to the study treatment. All interpretations 692 Page 22 of 47 Version: 2.1 04-Nov-2019 of study results will initially be done in a blinded manner by developing two interpretations of 693 the results. One interpretation will assume treatment A is iodine povacrylex (0.7% free iodine) in 694 74% isopropyl alcohol, the other interpretation will assume it is 2% CHG in 70% isopropyl 695 alcohol. Once the data interpretations for each assumption are finalized, the data will be 696 unblinded and the correct interpretation will be accepted. 35 697 698 4.6 Description of the Interventions 699 4.6.1 Initial Run-In Phase 700 Prior to initiating patient recruitment, each clinical site will begin using their assigned pre-701 operative antiseptic skin solution for eligible fracture surgeries (run-in period) to ensure that 702 acceptable compliance is met before initiating participant enrollment. Acceptable compliance 703 during the run-in phase will be defined as at surgeon, solution used, rationale for not using the assigned pre-operative antiseptic skin 714 solution). This portion of the study protocol is for quality assurance during the initial 715 implementation of the trial procedures. Fracture surgeries reviewed during the run-in phase will 716 not be included in the trial. Similarly, these patients will not be approached for informed consent 717 and no individual patient-level data will be submitted. CEO Methods Center personnel will 718 review the weekly reports with each of the clinical sites and develop strategies, as needed, to 719 ensure acceptable compliance during the run-in phase. This weekly communication will prevent 720 any delays in transitioning to the participant enrollment phase. 721 722 4.6.2 First Intervention Phase 723 Once the initial run-in phase is completed, participant recruitment will begin with the clinical 724 sites continuing to use the same pre-operative antiseptic skin solution for all eligible fracture 725 surgeries within the open and closed fracture populations over a two-month period. Patients will 726 receive the initially allocated treatment solution for all of their fracture management surgeries, 727 including repeat planned surgeries, even if a planned subsequent surgery occurs during a 728 recruitment period using the non-allocated solution. Participating clusters will ideally be able to 729 enroll a minimum of 77 open fracture patients and 314 closed lower extremity and pelvic 730 fractures per treatment over the total study recruitment duration (total of 154 open fracture 731 patients and 628 closed lower extremity and pelvic fracture patients), and it is anticipated that 732 most recruiting centers will exceed this minimum goal. Methods Center personnel will continue 733 to monitor compliance with the assigned pre-operative antiseptic skin solution over the 734 enrollment phase and work collaboratively with the clinical sites to minimize cases in which a 735 patient receives the incorrect solution. These monitoring activities will coincide with site-specific 736 procedures to maintain compliance for all patients, even those requiring multiple surgical 737 procedures. All assessments of compliance will be analyzed separately for the open and closed 738 fracture populations. If a fracture requires multiple surgeries and the correct solution is not 739 Page 23 of 47 Version: 2.1 04-Nov-2019 applied at each procedure, the patient will remain in the study and be analyzed using the 740 allocated solution (ITT principle). 741 742 4.6.3 Second Intervention Phase 743 Once the first intervention phase is completed, each site will crossover to the opposite study 744 solution. This crossover will occur simultaneously in the open and closed fracture populations. 745 There will be no run-in phase for the second solution and each site will need to develop local 746 procedures to ensure a successful crossover. Example procedures to minimize carry-forward of 747 first solution into the second solution phase include: 1) removing the bottles of the first solution 748 from the orthopaedic operating rooms; 2) changing study posters and notifications within the 749 operating rooms; and 3) performing the crossover during the middle of the week to provide a few 750 days' notice to the operating room staff and to avoid contamination of recent fracture patients 751 returning for repeat procedures (e.g., weekend admissions). The enrollment goals and procedures 752 will mirror the first intervention phase. Methods Center personnel will continue to monitor 753 compliance with the assigned pre-operative antiseptic skin solution over the enrollment phase 754 and work collaboratively with the clinical sites to reduce the risk of contamination. 755 756 4.6.4 Special Considerations for Ongoing Treatment Crossovers 757 Treatment allocation will continue to alternate between the study solutions, as outlined above, 758 for the remainder of study duration. Each intervention phase will be approximately two months 759 in duration, as agreed upon by the clinical site and CEO Methods Center personnel. The duration 760 may be modified to avoid crossovers on holidays, weekends, and other circumstances that could 761 threaten a successful crossover. The expected recruitment duration for the trial is approximately 762 24 months; however, some sites may have a shorter total recruitment duration (e.g., a 763 participating site that joins the trial later, high volume clinical sites, etc.). The two-month 764 enrollment periods will help account for seasonal variability in SSI incidence and their 765 associated infectious organisms, 36 as each crossover period will cover a season. In addition, for 766 those clinical sites enrolling beyond 12 months, the distribution of recruitment periods for each 767 solution may be seasonally matched by reversing the order of the alternating allocation after 12 768 months of recruitment. 769 770 4.6.5 Evaluation of Site Performance and Removal of Clinical Sites 771 After every two recruitment periods (approximately every four months), each site will be 772 evaluated for continued participation in the trial. Sites with <90% of eligible patients receiving 773 the allocated solution, differential adherence between study solutions, <95% follow-up of the 774 primary outcome, <90% follow-up of the secondary outcome, incomplete data submission, or 775 other threats to data quality or the validity of the study may be withdrawn from the trial. In the 776 event a site is withdrawn, data collection will be completed for all enrolled participants and these 777 data will be included in the final study analysis. 778 779 4.6.6 Application of Pre-Operative Antiseptic Skin Solutions 780 Each solution will be applied to the skin and allowed to dry for a minimum of three minutes. 781 While the application and minimum drying time for both study solutions are very similar, local 782 study personnel will provide standardized in-service (training) for orthopaedic surgeons, 783 operating room technicians, and nurses at each participating hospital prior to the initial run-in 784 phase. This training should include reviewing the manufacturers' directions for use to help 785 minimize incorrect application at clinical sites that may not routinely use both solutions. In 786 Page 24 of 47 Version: 2.1 04-Nov-2019 addition, the manufacturers may also provide demonstration videos and posters for continued 787 refresher training for each solution. 788 789 The study protocol will mandate the antiseptic skin solution to be used in each intervention phase 790 (Sections 4.4, 4.6.1, 4.6.2, 4.6.3, and 4.6.4); however, the protocol will remain pragmatic to 791 variability in the actual application of the solutions and other co-intervention steps performed 792 during the entire pre-operative skin preparation process performed in the operating room. Based 793 on individual surgeon preference, this often includes mechanically removing visible dirt or 794 debris with a scrub brush, and/or cleaning the limb with isopropyl alcohol or an antiseptic scrub 795 solution. These additional skin preparation steps will be permitted provided that: 1) the final skin 796 preparation step prior to surgical incision is the application of the allocated antiseptic solution; 797 and, 2) participating surgeons continue to use the same skin preparation co-interventions in both 798 intervention phases. Co-interventions that contain the opposite active ingredient from the current 799 intervention phase (e.g., using a CHG scrub brush during the iodine intervention phase, or 800 conversely, using an iodine scrub during the CHG intervention phase) should be avoided; 801 however, deviations from this recommendation will be permitted to maintain pragmatic 802 flexibility of delivery and reflect real-world clinical practice. The details of all operating room 803 antiseptic co-interventions will be documented. 804 805 4.6.7 Patients with Multiple Planned Surgeries 806 Fracture patients who require multiple planned surgeries for their injury will receive the same 807 antiseptic skin solution during each subsequent procedure. Methods Center personnel will work 808 with each of the clinical sites to develop strategies for minimizing crossovers. For example, for 809 patients who require multiple surgeries and are enrolled within 14 days of the anticipated end of 810 a recruitment period, study personnel will develop local procedures to identify these patients as 811 study participants and indicate the patient's allocated antiseptic solution in the medical chart and 812 CRFs. 813 814 4.6.8 Iodophor Antiseptic Solution 815 The iodine-based treatment intervention will be an antiseptic solution comprised of iodine 816 povacrylex (0.7% free iodine) in 74% isopropyl alcohol. 3M™ DuraPrep™ [3M Health Care, St 817 Paul, MN], will be the commercial product used. Clinical site personnel will store and handle the 818 product as per the manufacturers' recommendations. Operating room personnel will apply the 819 solution to the operative site as the final preoperative skin antisepsis preparation immediately 820 prior to commencing surgical fixation. They will apply the solution as per manufacturer's 821 directions for use (e.g., technique of application, duration of application, drying time, drying 822 techniques, replacement of draping, etc.). 823 824 4.6.9 CHG Antiseptic Solution 825 The CHG solution will contain 2% CHG in 70% isopropyl alcohol as the only active ingredients. 826 Products that list other inactive ingredients will be permitted. ChloraPrep® [CareFusion Inc., 827 Leawood, KS, USA] will be the commercial product used. Clinical site personnel will store and 828 handle the product as per the manufacturers' recommendations. Operating room personnel will 829 apply the solution to the operative site as the final preoperative skin antisepsis preparation 830 immediately prior to commencing surgical fixation. They will apply the solution as per 831 manufacturer's directions (e.g., technique of application, duration of application, drying time, 832 replacement of draping, etc.).

Perioperative Co-Interventions 835
To optimize the internal validity of the trial findings, key details of co-interventions known to 836 influence the incidence of SSIs will be documented. Hospitals typically implement standard 837 procedures to achieve quality process benchmarks designed to minimize SSIs. These benchmarks 838 are outlined in several similar guidelines such as the Joint Commission's Surgical Care 839 Improvement Project 10 Core Measures to prevent SSI, the Society for Healthcare Epidemiology 840 of America compendium to prevent SSI, and prevention guides from the Institute for Healthcare 841 Improvement and the Association of periOperative Registered Nurses. While these guidelines 842 mandate core benchmark processes to minimize SSI, it is not practical or generalizable for the 843 trial protocol to standardize the steps taken or co-interventions performed to achieve these core 844 measures, since each participating hospital will already have their own implemented procedures. 845 This is the primary rationale for the cluster-crossover design, in which each participating hospital 846 will act as its own control for the effect of co-interventions. Therefore, four key approaches to 847 account for and limit the potential differential application of co-interventions during the study 848 periods will be performed: 1) study periods for each intervention are kept relatively short to 849 improve the likelihood that newly implemented co-interventions will be equally distributed  (Table 3). Since the management of some 863 fractures may have more than one operative procedure as part of an intentionally staged surgical 864 plan (e.g., multiple irrigation and debridements, wound closures, temporary stabilization 865 surgeries, definitive fixation surgery), the primary outcome will include any SSI event from the 866 date of fracture to the end of the 30-and 90-day post-operative surveillance periods from their 867 definitive fracture management surgery. For participants with multiple fracture regions, the date 868 of the definitive fracture management surgery will be matched to the fracture region with the 869 SSI. 870 871 Description 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 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

875
The CDC criteria for classifying SSIs will be followed. If multiple tissue levels are involved in 876 the infection, the type of SSI (superficial incisional, deep incisional, or organ/space) reported 877 will reflect the deepest tissue layer involved in the infection during the surveillance period. The 878 date of event will be the date that the participant met criteria for the deepest level of infection 879 using the following procedures: 1) report infection that involves the organ/space as an 880 organ/space SSI, whether or not it also involves the superficial or deep incision sites and 2) 881 report infection that involves the superficial and deep incisional sites as a deep incisional SSI. 882 The most relevant National Healthcare Safety Network Organ/Space SSI classifications are 883 summarized in Table 4. Whenever possible, the treating surgeon or study personnel should take 884 photos of the infected region to facilitate the adjudication process. 885 886 The secondary outcome is unplanned fracture-related reoperation within 12 months of the 900 fracture(s). This outcome has been used in previous fracture trials and is defined as any 901 unplanned surgery that occurred from the time of injury to 12 months post-injury that is 902 associated with an infection at the operative site or contiguous to it, a wound-healing problem, or 903 a fracture delayed union or nonunion. The second exploratory outcome is SSI using the CDC criteria within 12 months of the fracture. 940 This secondary outcome will use the same diagnostic CDC reporting criteria for the primary 941 outcome (Tables 3 and 4); however, the timeframe for this outcome will be expanded to include 942 all SSIs that occur within 12 months of fracture. Similar to the rationale for using the FRI 943 outcome, and the recommendations for a minimum of 12 months follow-up for orthopaedic 944 fracture outcomes 40 , this expanded timeframe will detect infections that occur beyond the 945 standard CDC surveillance reporting periods. This modification of the CDC reporting periods 946 has been used in previous orthopaedic fracture trials. 4,41 947 948 An infection preventionist nurse and an orthopaedic surgeon member of the Adjudication 949 Committee will review all reported SSIs to determine if they meet the FRI confirmatory criteria 950 and / or the CDC criteria following the processes described above (see Section 4.8.1 Surgical data and in-hospital data will be collected throughout the participant's hospital stay. 963 Detailed information will be collected regarding the surgical management of their fracture(s), 964 Page 29 of 47 Version: 2.1 04-Nov-2019 including the timing of the surgery(ies) and the method of initial and definitive fracture 965 treatment. For open fracture regions, study personnel will also record the use of staged 966 debridements, the presence or lack of skin closure between debridements, and the use of local 967 antibiotics at the wound. Lastly, study personnel will record the use of negative pressure wound 968 therapy for open wounds or in the presence of open wounds surgically closed. These treatment 969 decisions are hypothesized to be associated markers of injury severity and potential confounders 970 of the study interventions. 971 972 Study participants will be followed at 6 weeks, 3 months, 6 months, 9 months, and 12 months 973 from their fracture. SSIs and unplanned fracture-related reoperations will be identified at the 974 time of diagnosis/occurrence and/or during each participant's clinical assessment and medical 975 record review that will occur during their routine outpatient clinic visits ( Table 2). Detailed 976 information on the SSI including the date of diagnosis, participant signs and symptoms, culture 977 test results, method of treatment(s), and date of resolution will be collected. Study personnel will 978 also record details about the participants' reoperations on the CRFs (e.g., date of reoperation, 979 type of procedure, reason for procedure, etc.). In cases where the participant does not return to 980 the clinic, study personnel will contact the participant by telephone, text, email, and standard 981 mail and will review their medical record for any SSIs or fracture-related reoperations. If the 982 participant reports being treated at another hospital, study personnel will obtain the medical 983 records from the other hospital. We have used this approach in our other multi-center trials (e.g., 984 SPRINT, TRUST, FLOW, FAITH, HEALTH, etc. Several strategies may be used to maximize follow-up including: 1) at the time of enrollment, 992 each participant will provide their own telephone number, as well as the name and address of a 993 primary care physician, and the names and phone numbers of three people at different addresses 994 with whom the participant does not live with and who are likely to be aware of the participant's 995 whereabouts; 2) participants will receive a reminder card upon discharge for their next follow up 996 visit by the clinical site study personnel; 3) participants will receive text message reminders; 4) Table 5 and Table 6 below outlines the summary of the initial sample size assumptions. These 1061 sample size estimates are rounded up to the nearest multiple of 20 to ensure balance among 10 1062 clinical sites and two interventions. 1063 1064  approached and reported in accordance with best practices and guidelines for subgroup 1124 analyses. 33,52-54 Table 8 below shows a summary of the subgroup analysis objectives,  1125 corresponding outcomes, hypotheses, and methods of analysis for each fracture population. 1126 1127 Assessment of the sensitivity or robustness of the findings to the key assumptions is essential in 1132 trials. The following sensitivity analyses may be conducted to explore the effects of alternative 1133 analysis models, alternative missing data approaches, balancing prognostic imbalance, as-treated 1134 analyses, variability in co-interventions, and alternative definitions of SSI. 1135 1136