Pre-operative Aqueous Antiseptic Skin Solutions in Open Fractures (Aqueous-PREP)

Aqueous-PREP: A Pragmatic Randomized Trial Evaluating Pre-operative Aqueous Antiseptic Skin Solutions in Open Fractures

The prevention of infection is the single most important goal influencing peri-operative care of patients with open fractures. Standard practice in the management of open 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 open fracture surgery.

Study Overview

• Status: Completed
• Conditions: Surgical Site Infection; Unplanned Fracture-Related Reoperation; Open Appendicular Fracture
• Intervention / Treatment: Drug: 10% povidone-iodine (1% free iodine) in purified water; Drug: 4% chlorhexidine gluconate (CHG) in purified water

• Study Type: Interventional
• Enrollment (Actual): 1638
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton Health Sciences
    • Hamilton, Ontario, Canada, L8L 8E7
      • McMaster University, Center for Evidence-Based Orthopaedics
• Spain
  • Barcelona, Spain
    • Vall d'Hebron University Hospital
  • Barcelona, Spain
    • Hospital Parc Taulí de Sabadell
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • The CORE Institute / Banner University Medical Center
    • Tucson, Arizona, United States, 85721
      • Banner - University Medical Center Tucson
  • California
    • San Francisco, California, United States, 94143
      • University of California San Francisco
  • Florida
    • Gainesville, Florida, United States, 32611
      • University of Florida
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Methodist Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland, R Adams Cowley Shock Trauma Center
  • Ohio
    • Dayton, Ohio, United States, 45409
      • Wright State University / Miami Valley Hospital
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Greenville Health System
  • Tennessee
    • Nashville, Tennessee, United States, 37240
      • Vanderbilt University
  • Texas
    • Fort Sam Houston, Texas, United States, 78234
      • San Antonio Military Medical Center
    • Houston, Texas, United States, 77030
      • McGovern Medical School at University of Texas Health Science Center Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

The 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) (e.g., 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 exclusion criteria are:

1. Patients that did not or will not receive the allocated pre-operative surgical preparation solution due to a medical contraindication.
2. Received previous surgical debridement or management of their open fracture at a non-participating hospital or clinic.
3. Open fracture managed outside of the participating orthopaedic service (e.g., hand fracture managed by plastic surgeon).
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. Previous enrollment in a PREP-IT trial.
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. Excluded due to sampling strategy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 10% povidone-iodine (1% free iodine) in purified water; The povidone-iodine solution will contain 10% povidone-iodine (1% free iodine) in purified water as the only active ingredient. 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.).	Drug: 10% povidone-iodine (1% free iodine) in purified water; Participant recruitment will begin with the clinical sites using their assigned pre-operative antiseptic skin solution for all open fracture surgeries for a two-month period.; Drug: 4% chlorhexidine gluconate (CHG) in purified water; Once the first intervention phase is completed, each site will crossover to the opposite study solution. Each site will need to develop local procedures to ensure a successful crossover. They will use the second solution for all open fracture surgeries for a two-month period, and will then crossover back to the solution in the first intervention phase.
Experimental: 4% chlorhexidine gluconate (CHG) in purified water; The CHG solution will contain 4% CHG in purified water as the only active ingredient. 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.).	Drug: 10% povidone-iodine (1% free iodine) in purified water; Participant recruitment will begin with the clinical sites using their assigned pre-operative antiseptic skin solution for all open fracture surgeries for a two-month period.; Drug: 4% chlorhexidine gluconate (CHG) in purified water; Once the first intervention phase is completed, each site will crossover to the opposite study solution. Each site will need to develop local procedures to ensure a successful crossover. They will use the second solution for all open fracture surgeries for a two-month period, and will then crossover back to the solution in the first intervention phase.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Superficial Incisional Surgical Site Infection (SSI)	Guided by the Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network reporting criteria (2017): Date of event for infection may occur from the date of fracture to 30 days after the definitive fracture management surgery; AND involves only skin and subcutaneous tissue of the incision; AND patient has at least one of the following: purulent drainage from the superficial incision.; 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; superficial incision that is deliberately opened by a surgeon, 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.; diagnosis of a superficial incisional SSI by the surgeon.	Within 30 days of the patient's last planned fracture management surgery
Number of Participants With a Deep Incisional or Organ/Space Infection	Guided by CDC's National Healthcare Safety Network Surgical Site Infection reporting criteria (2017): Deep Incisional Infection: Occurs within 90 days post definitive fracture management; & involves fascial/muscle layers; & has at least one of the following: deep incision purulent drainage; a deep incision that dehisces, or is opened by a surgeon, and organism is identified by microbiologic testing; or microbiologic testing is not performed & has at least one of the following: fever (> 38 °C); localized pain or tenderness; other evidence of deep incision infection on anatomical exam or imaging test Organ/Space Infection: Occurs within 90 days post definitive fracture management; & involves any part of the body deeper than the fascial/muscle layers; & has at least one of the following: organ/space purulent drainage; organisms in organ/space identified by microbiologic testing; other evidence of organ/space infection on anatomical exam or imaging test	Within 90 days of the patient's last planned fracture management surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With an Unplanned Fracture-Related Reoperation	Common examples include any unplanned fracture-related surgery that is associated with an infection at the operative site or contiguous to it, a wound-healing problem, or a fracture delayed union or non-union.	Within 12 months of the patient's last planned operation

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: United States Department of Defense; McMaster University
• Investigators: Principal Investigator: Gerard Slobogean, MD, University of Maryland Shock Trauma Center

Publications and helpful links

General Publications

• O'Hara NN, Heels-Ansdell D, Bzovsky S, Dodds S, Thabane L, Bhandari M, Guyatt G, Devereaux PJ, Slobogean GP, Sprague S; PREP-IT Investigators. A pragmatic randomized trial evaluating pre-operative aqueous antiseptic skin solutions in open fractures (Aqueous-PREP): statistical analysis plan. Trials. 2022 Sep 12;23(1):772. doi: 10.1186/s13063-022-06541-0.
• Sprague S, Guyatt P, Bzovsky S, Nguyen U, Bhandari M, Thabane L, Petrisor B, Johal HS, Leonard J, Dodds S, Mossuto F, O'Toole RV, Howe A, Demyanovich HK, Camara M, O'Hara NN, Slobogean GP; PREP-IT Investigators. Pragmatic randomized trial evaluating pre-operative aqueous antiseptic skin solution in open fractures (Aqueous-PREP): the feasibility of a cluster randomized crossover study. Pilot Feasibility Stud. 2021 Mar 1;7(1):61. doi: 10.1186/s40814-021-00800-8.
• Sprague S, Scott T, Dodds S, Pogorzelski D, McKay P, Harris AD, Wood A, Thabane L, Bhandari M, Mehta S, Gaski G, Boulton C, Marcano-Fernandez F, Guerra-Farfan E, Hebden J, O'Hara LM, Slobogean GP; PREP-IT Investigators. Cluster identification, selection, and description in cluster randomized crossover trials: the PREP-IT trials. Trials. 2020 Aug 12;21(1):712. doi: 10.1186/s13063-020-04611-9. Erratum In: Trials. 2020 Sep 30;21(1):821.
• Program of Randomized Trials to Evaluate Pre-operative Antiseptic Skin Solutions in Orthopaedic Trauma (PREP-IT) Investigators; Slobogean GP, Sprague S, Wells J, Bhandari M, Rojas A, Garibaldi A, Wood A, Howe A, Harris AD, Petrisor BA, Mullins DC, Pogorzelski D, Marvel D, Heels-Ansdell D, Mossuto F, Grissom F, Del Fabbro G, Guyatt GH, Della Rocca GJ, Demyanovich HK, Gitajn IL, Palmer J, D'Alleyrand JC, Friedrich J, Rivera J, Hebden J, Rudnicki J, Fowler J, Jeray KJ, Thabane L, Marchand L, O'Hara LM, Joshi MG, Talbot M, Camara M, Szasz OP, O'Hara NN, McKay P, Devereaux PJ, O'Toole RV, Zura R, Morshed S, Dodds S, Li S, Tanner SL, Scott T, Nguyen U. Effectiveness of Iodophor vs Chlorhexidine Solutions for Surgical Site Infections and Unplanned Reoperations for Patients Who Underwent Fracture Repair: The PREP-IT Master Protocol. JAMA Netw Open. 2020 Apr 1;3(4):e202215. doi: 10.1001/jamanetworkopen.2020.2215. Erratum In: JAMA Netw Open. 2020 Sep 1;3(9):e2021571. JAMA Netw Open. 2021 Jun 1;4(6):e2117240.
• PREP-IT Investigators. Aqueous skin antisepsis before surgical fixation of open fractures (Aqueous-PREP): a multiple-period, cluster-randomised, crossover trial. Lancet. 2022 Oct 15;400(10360):1334-1344. doi: 10.1016/S0140-6736(22)01652-X. Erratum In: Lancet. 2023 Dec 17;400(10369):2198.

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2018
• Primary Completion (Actual): October 19, 2021
• Study Completion (Actual): June 27, 2022

Study Registration Dates

• First Submitted: December 20, 2017
• First Submitted That Met QC Criteria: December 20, 2017
• First Posted (Actual): December 28, 2017

Study Record Updates

• Last Update Posted (Actual): March 31, 2023
• Last Update Submitted That Met QC Criteria: March 6, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Surgical Site Infection; Povidone-iodine; Open Fracture; Chlorhexidine gluconate; Peri-operative Preparation Solutions
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Postoperative Complications; Wounds and Injuries; Wound Infection; Fractures, Bone; Surgical Wound Infection; Fractures, Open; Physiological Effects of Drugs; Anti-Infective Agents, Local; Anti-Infective Agents; Dermatologic Agents; Trace Elements; Micronutrients; Disinfectants; Plasma Substitutes; Blood Substitutes; Iodine; Chlorhexidine; Povidone-Iodine; Povidone; Chlorhexidine gluconate
• Other Study ID Numbers: HP-00078470

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes