CClinicalTrials.gg
CompletedNCT03385304Aqueous-PREPUpdated Mar 31, 2023Results posted

Pre-operative Aqueous Antiseptic Skin Solutions in Open Fractures

A Phase 4 interventional study of 10% povidone-iodine (1% free iodine) in purified water and 4% chlorhexidine gluconate (CHG) in purified water in Surgical Site Infection, Unplanned Fracture-Related Reoperation and Open Appendicular Fracture, sponsored by University of Maryland, Baltimore. Completed at 15 sites in 3 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-03-31.

Sponsored by University of Maryland, Baltimore · Phase 4, Interventional, and Treatment

Phase
Phase 4
Study type
Interventional
Enrollment
1,638
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study summary

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.

02

Conditions studied

  • Surgical Site Infection
  • Unplanned Fracture-Related Reoperation
  • Open Appendicular Fracture

Keywords

  • Surgical Site Infection
  • Open Fracture
  • Povidone-iodine
  • Chlorhexidine gluconate
  • Peri-operative Preparation Solutions
03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility criteria

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.
04

Study design

Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Crossover assignment
Masking
Single (Outcomes assessor)
Enrollment
1,638 participants (actual)

Study arms

  • 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 · Drug: 4% chlorhexidine gluconate (CHG) in purified water

  • 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 · Drug: 4% chlorhexidine gluconate (CHG) in purified water

Interventions

  • Drug10% 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.

  • Drug4% 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.

05

What researchers measure

Primary outcomes

  1. 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: 1. purulent drainage from the superficial incision. 2. 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 3. 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. 4. diagnosis of a superficial incisional SSI by the surgeon.

    Time frame: Within 30 days of the patient's last planned fracture management surgery

  2. 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: 1. deep incision purulent drainage 2. 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 3. 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: 1. organ/space purulent drainage 2. organisms in organ/space identified by microbiologic testing 3. other evidence of organ/space infection on anatomical exam or imaging test

    Time frame: Within 90 days of the patient's last planned fracture management surgery

Secondary outcomes

  1. 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.

    Time frame: Within 12 months of the patient's last planned operation

06

Results

Posted Mar 31, 2023
Limitations and caveats
The uncontrolled use of adjunctive skin preparations before final antisepsis is a potential limitation of our study design. Although the use of a prewash with adjunctive alcohol was similarly distributed between the treatment groups, post-randomization confounding from this practice might exist. The trial has other limitations, including unmasked treatment allocation and the decision to initiate each recruitment site as soon as possible.

Participant flow

Recruitment occurred between April 8, 2018, and June 8, 2021 at 14 hospitals in Canada, Spain and the USA. Eligible patients were adults aged 18 years or older with an open extremity fracture treated with a surgical fixation implant. For inclusion, the open fracture required formal surgical debridement within 72 hours of the injury.

Participant flow — Overall Study
Milestone10% Povidone-iodine (1% Free Iodine) in Purified Water4% Chlorhexidine Gluconate (CHG) in Purified Water
Started828810
Months 1-2114108
Months 3-4102104
Months 5-69853
Months 7-85068
Months 9-109163
Months 11-127275
Months 13-146250
Months 15-163855
Months 17-183844
Months 19-203246
Months 21-225040
Months 23-243064
Months 25-262214
Months 27-282118
Months 29-3008
Months 31-3280
Completed787784
Not completed4126
Withdrew: Death197
Withdrew: Lost to follow-up1714
Withdrew: Withdrawal by subject32
Withdrew: Incarceration23

Outcome measures

PrimaryNumber 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: 1. purulent drainage from the superficial incision. 2. 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 3. 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. 4. diagnosis of a superficial incisional SSI by the surgeon.

Time frame:
Within 30 days of the patient's last planned fracture management surgery
Reported as:
Count of participants · Participants
Number of Participants With a Superficial Incisional Surgical Site Infection (SSI)
Participants10% Povidone-iodine (1% Free Iodine) in Purified Water4% Chlorhexidine Gluconate (CHG) in Purified Water
Number of Participants With a Superficial Incisional Surgical Site Infection (SSI)137
PrimaryNumber 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: 1. deep incision purulent drainage 2. 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 3. 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: 1. organ/space purulent drainage 2. organisms in organ/space identified by microbiologic testing 3. other evidence of organ/space infection on anatomical exam or imaging test

Time frame:
Within 90 days of the patient's last planned fracture management surgery
Reported as:
Count of participants · Participants
Number of Participants With a Deep Incisional or Organ/Space Infection
Participants10% Povidone-iodine (1% Free Iodine) in Purified Water4% Chlorhexidine Gluconate (CHG) in Purified Water
Number of Participants With a Deep Incisional or Organ/Space Infection4651
SecondaryNumber 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.

Time frame:
Within 12 months of the patient's last planned operation
Reported as:
Count of participants · Participants
Number of Participants With an Unplanned Fracture-Related Reoperation
Participants10% Povidone-iodine (1% Free Iodine) in Purified Water4% Chlorhexidine Gluconate (CHG) in Purified Water
Number of Participants With an Unplanned Fracture-Related Reoperation118115

Adverse events

Collected over 1 year post injury. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
10% Povidone-iodine (1% Free Iodine) in Purified Water19/828 (2.3%)365/828 (44.1%)—
4% Chlorhexidine Gluconate (CHG) in Purified Water7/810 (0.9%)368/810 (45.4%)—
Most frequent serious events
Most frequent serious events
Event10% Povidone-iodine (1% Free Iodine) in Purified Water4% Chlorhexidine Gluconate (CHG) in Purified Water
Study Fracture Related ComplicationMusculoskeletal and connective tissue disorders178/828192/810
OtherGeneral disorders95/82869/810
Non-Study Fracture Related ComplicationMusculoskeletal and connective tissue disorders23/82831/810
PulmonaryRespiratory, thoracic and mediastinal disorders26/82825/810
VascularVascular disorders11/82812/810
Gastro-IntestinalGastrointestinal disorders10/82812/810
RenalRenal and urinary disorders10/82810/810
CardiacCardiac disorders7/8289/810
NeurologicalNervous system disorders5/8288/810

Baseline characteristics

Age, Continuous
Age, Continuous(years)10% Povidone-iodine (1% Free Iodine) in Purified Water4% Chlorhexidine Gluconate (CHG) in Purified WaterTotal
Age45.2 ± 18.244.5 ± 17.944.9 ± 18.1
Sex: Female, Male
Sex: Female, Male(Participants)10% Povidone-iodine (1% Free Iodine) in Purified Water4% Chlorhexidine Gluconate (CHG) in Purified WaterTotal
Female324303627
Male5045071011
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)10% Povidone-iodine (1% Free Iodine) in Purified Water4% Chlorhexidine Gluconate (CHG) in Purified WaterTotal
Race — White6656241289
Race — Black124137261
Race — Central or South American102030
Race — Asian81018
Race — Prefer not to answer71118
Race — Indigenous11516
Race — Multiracial325
Race — Native Hawaiian or Pacific Islander011
BMI
BMI(Participants)10% Povidone-iodine (1% Free Iodine) in Purified Water4% Chlorhexidine Gluconate (CHG) in Purified WaterTotal
Underweight (<18.5 kg/m^2)91019
Healthy weight (18.5 - 24.9 kg/m^2)243200443
Overweight (25.0-29.9 kg/m^2)247271518
Obesity (>30.0 kg/m^2)329329658
Diabetes of any type
Diabetes of any type(Participants)10% Povidone-iodine (1% Free Iodine) in Purified Water4% Chlorhexidine Gluconate (CHG) in Purified WaterTotal
Count of participants9476170
Current smoker
Current smoker(Participants)10% Povidone-iodine (1% Free Iodine) in Purified Water4% Chlorhexidine Gluconate (CHG) in Purified WaterTotal
Count of participants293274567
American Society of Anesthesiologist (ASA) Physical Score
American Society of Anesthesiologist (ASA) Physical Score(Participants)10% Povidone-iodine (1% Free Iodine) in Purified Water4% Chlorhexidine Gluconate (CHG) in Purified WaterTotal
Class I or II423436859
Class III or higher405374779
Number of included open fractures per participant
Number of included open fractures per participant(Participants)10% Povidone-iodine (1% Free Iodine) in Purified Water4% Chlorhexidine Gluconate (CHG) in Purified WaterTotal
One7757531528
Two445195
Three9615
07

Study locations

15 sites
  • The CORE Institute / Banner University Medical Center
    Phoenix, Arizona 85006, United States
  • Banner - University Medical Center Tucson
    Tucson, Arizona 85721, United States
  • University of California San Francisco
    San Francisco, California 94143, United States
  • University of Florida
    Gainesville, Florida 32611, United States
  • Indiana University Health Methodist Hospital
    Indianapolis, Indiana 46202, United States
  • University of Maryland, R Adams Cowley Shock Trauma Center
    Baltimore, Maryland 21201, United States
  • Wright State University / Miami Valley Hospital
    Dayton, Ohio 45409, United States
  • Greenville Health System
    Greenville, South Carolina 29605, United States
  • Vanderbilt University
    Nashville, Tennessee 37240, United States
  • San Antonio Military Medical Center
    Fort Sam Houston, Texas 78234, United States
  • McGovern Medical School at University of Texas Health Science Center Houston
    Houston, Texas 77030, United States
  • Hamilton Health Sciences
    Hamilton, Ontario L8L 2X2, Canada
  • McMaster University, Center for Evidence-Based Orthopaedics
    Hamilton, Ontario L8L 8E7, Canada
  • Hospital Parc Tauli de Sabadell
    Barcelona, Spain
  • Vall d'Hebron University Hospital
    Barcelona, Spain
08

References and documents

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. PubMed 36096826 ↗
  • 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. doi: 10.1016/S0140-6736(22)02540-5. PubMed 36244384 ↗
  • 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. PubMed 33648577 ↗
  • 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. doi: 10.1186/s13063-020-04767-4. PubMed 32787892 ↗
  • 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. doi: 10.1001/jamanetworkopen.2020.21571. JAMA Netw Open. 2021 Jun 1;4(6):e2117240. doi: 10.1001/jamanetworkopen.2021.17240. PubMed 32259266 ↗

Study documents

  • Protocol and statistical analysis plan · Nov 4, 2019

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

09

Registry details

Key details

Study ID
NCT03385304
Lead sponsor
University of Maryland, Baltimore
Collaborators
McMaster University, United States Department of Defense
Responsible party
Gerard Slobogean (Assistant Professor, Department of Orthopaedics, University of Maryland, Baltimore) — Principal investigator
First posted
Dec 28, 2017
Start date
Apr 8, 2018
Primary completion
Oct 19, 2021
Completion
Jun 27, 2022
Results posted
Mar 31, 2023
Last update
Mar 31, 2023

Study contacts

Gerard Slobogean, MD
principal investigator · University of Maryland, Baltimore
Sheila Sprague, PhD
principal investigator · McMaster University
Mohit Bhandari, MD
principal investigator · McMaster University

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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