Antibiotic Therapy to Reduce Infection after Operative Treatment of Fractures: A Controlled Trial

1. Local Antibiotic Therapy to Reduce Infection after Operative Treatment of Fractures at High Risk of Infection: A Multicenter, Randomized, Controlled Trial Study Procedures Training Tuesday, February 10, 2015 PI: Robert V. O’Toole, MD (University of Maryland Shock Trauma)

2. VANCO Study Team Contacts

3. Agenda • Screening & Enrollment Procedures • Baseline Data Collection • Surgeon Training/Vanco Powder Application • Follow-up Data Collection • Event Reporting • Implementation Questions • Monitoring • Invoicing

4. Screening • Screening criteria • Closed or Open (Grade I, II, or III) tibial plateau or pilon (distal tibial plafond) fractures requiring operative treatment with plate and screw fixation • 18-80 years of age, inclusive • Screening process • Determine which members of your study team will be responsible for identifying all admitted patients who meet screening criteria. • Complete CRF00 (Screening Form) for ALL patients meeting screening criteria. Use the CRF00 as a mechanism for documenting and determining study eligibility. • Screening resources • Screening app: www.lookup.metrc.org • Study-specific screening cards (let Tara know if you want these)

5. For Sites Participating in PAIN or OXY in addition to VANCO Patients Meeting Screening Criteria for PAIN, VANCO, & OXYGEN (e.g., pilon) Order of Enrollment Priority: (1) PAIN, (2) VANCO, (3) OXYGEN • Enroll in PAIN • Indicate on VAN (#15) and OXY (#18) CRF00 that patient is enrolled in PAIN and screening is complete Complete CRF00, Screening Forms for all three studies Eligible for PAIN Study • Enroll in VANCO • Indicate on OXY (#18) CRF00 that patient is enrolled in VANCO and screening is complete Ineligible for PAIN and Eligible for VANCO • Enroll in OXY Ineligible for VANCO and Eligible for OXY (calcs)

6. Inclusion Criteria • Tibial plateau (41B and 41C)or tibialpilon(43B and 43C) fractures with the following characteristics and also requiring operative treatment with plate and screw fixation • Closed fx, initially treated with external fixation (with or without limited internal fixation) because of swelling and high energy nature of the fx, and treated definitively in a delayed fashion more than 3 days later once swelling has resolved adequately • Open fx, Gustilo types I, II, or IIIA, regardless of timing of definitive treatment or use of initial external fixator • Open or closed fx, associated with ipsilateral leg compartment syndrome treated with fasciotomy wound(s), regardless of timing of definitive treatment and use of initial external fixator • Between 18 and 80 years of age, inclusive • Note: OTA 43A’s, which are sometimes called “extra-articular pilons” are not included; OTA 41A’s which are extra-articular plateaus are not included

7. Patients may have… • Co-existing infection not at study fracture site, with or without antibiotic treatment • Risk factors for infection including diabetes, immunosuppression from steroids or other medications, HIV, or other infections • Head injury • Initial treatment with a temporary external fixator prior to randomization • Portion of fixation prior to definitive plate fixation (e.g., fibula fixation in pilon or percutaneous screws across a tibial plateau fracture), at any initial surgery before randomization for definitive fixation • Other orthopaedic and non-orthopaedic injuries • Pre-existing musculoskeletal injuries, be non-ambulators, or have spinal cord injuries

8. Exclusion Criteria • Study injury that is infected prior to definitive fixation surgery, as designated by treating physician per CDC criteria • Study fracture has already been definitively fixed • Massive myonecrosis from ipsilateral leg compartment syndrome • Pregnancy • Patient speaks neither English nor Spanish • Patient has a history of allergy to Vancomycin or a previous reaction to Vancomycin (e.g., Red Man’s Syndrome) • Patient is likely to have severe problems maintaining follow-up

9. Patients w/ Abnormal Kidney Function • Abnormal kidney function is not currently an exclusion criterion • However, if you have an otherwise eligible patient who is already experiencing serious renal insufficiency or renal failure, and your PI does not feel comfortable putting the patient in the study, you can use CRF00 item #15: “Is the patient able to participate in this study?” Select “No, due to other reason”, and then specify the reason. • Otherwise, we are tracking medical history on CRF03, the Medical History Form, and we are tracking complications during index hospitalization as well as follow-up

10. Consent & Enrollment • 1,000 patients will be enrolled (500 per study arm) over 12 month period • Consent Process: • Research Coordinator and Attending Surgeon should approach eligible patients for consent as soon as possible following determination of their eligibility. • Ideally, this process should occur during index hospitalization. Consent should always be obtained prior to definitive fixation surgery (high energy tibial plateau and pilon fractures often definitively fixed 1-2 weeks after injury to allow for swelling to resolve). • Once an eligible patient consents to the study, the Research Coordinator should complete the rest of CRF00 and then enter it into REDCap. The patient will be electronically randomized. • Patients in the VANCO study should not be co-enrolled in any other studies, METRC or non-METRC (FDA requirement)

11. Blinding • Patients • The protocol says the following: • “Randomization will occur at the time of surgery so that the patient will not be aware pre-operatively or post-operatively which treatment group he or she is in.” • However, we did not indicate in the prototype consent document that patients would be blinded • If a patient asks whether or not he or she is in the treatment or control arm, you may tell him or her the assignment • If they don’t ask… no need to tell them • Surgeons • It is not practical to blind the study surgeons. Since the primary outcome is deep surgical site infection, which requires a return to the operating room (very objective outcome), lack of blinding should not be problematic.

12. Use of LARs • Use of legally authorized representatives is permissible in this study • An LAR with reasonable knowledge of the potential participant should be approached for consent on the patient’s behalf if one of the following is true: • Patient is unresponsive (and likely to remain so through period of definitive fixation) • Patient cannot adequately answer at least 2 questions and it is determined that the patient’s level of cognition is not likely to change before surgery

13. Baseline Data Collection • Participant characteristics • Injury characteristics • Fracture classification • Medical history/co-morbidities • Characteristics about hospital course and treatment received • Brief interview with the participant or his/her LAR • Blood sampling • Will occur as performed at all institutions with respect to standard clinical care per institutional practice • Typically includes pregnancy tests when appropriate, serum creatinine, and complete blood count at baseline. The labs may or may not include tests for fungi. • Name, strength, manufacturer and batch number for every vial of vancomycin used in this study… save those labels!

14. Local Toxicity Testing at UMD • We are also pilot testing Vancomycin levels within 24 hours of placement of powder in the operating room for the first 30 participants at University of Maryland, Shock Trauma • It is anticipated that the system levels will be undetectable or clinically insignificant based on prior literature • Dr. Bob O’Toole and Dr. Manjari Joshi plan to review the results of these blood draws in real-time   • Any adverse events identified over these samples will be reported to the IRB, the FDA, and the rest of the participating sites (via email). • The data will also be collected in REDCap and will be reviewed by the medical monitor, Dr. Marc Swiontkowski (letter on Study Materials page, too)

15. Surgeon Training • Dr. O’Toole will record a Surgeon Training presentation within the next week and the presentation will be posted to the METRC website • The training will cover: • Brief overview of background, rationale, specific aims, study outcomes, I&E criteria, screening & enrollment, and data collection basics • Commonly asked questions about application of the vancomycin powder during definitive fixation surgery (also included here on next few slides) • Each site will also receive a Certification Call with Dr. O’Toole • Call attendees: Dr. O’Toole, Site PI, Site RC, MCC Study Team members • Tara will work with each of you to schedule these calls after you are certified by the MCC to begin screening and enrollment • If you’d prefer to have a call earlier, please let us know and we will make arrangements to do so

16. Vanco Powder Application: Surgeon Q&A 1. I plan to conduct a staged definitive fixation procedure. Should I use the vancomycin powder during both surgeries, just the first, or just the last? • You should only use the local vancomycin powder during the final procedure. 2. How much vancomycin powder are we supposed to use? • 1,000 mg total should be used. 3. What if there are multiple incisions? Do we put it all in one incision, or do we spread it out? • You should split the total dose (1,000 mg) between the wounds that have a plate that you can get to. We will track which incisions you put the powder in on the CRFs.

17. Vanco Powder Application FAQs 4. Should I put the vanco powder on the plate, the soft tissue, or both? • The goal is to sterilize the plate and so you should have the vancomycin powder make as much contact with the plate as possible. 5. I’ve been using vanco powder anyway and I usually make it into a paste before applying it. Can I use this method in this study? • To minimize variation across sites, please use the powder form for the purposes of this study. Please remember to save the label from the vial of vancomycin powder! Give it to your Research Coordinator who will need to affix it to the CRF.

18. A Few Other Points for Surgeons… • You can use whatever manufacturer your institution standardly stocks • You should not use any other local antibiotics in the wound, e.g., beads, spacers • Beads, spacers, etc., may be used in earlier stages, but not in definitive fixation • Surgeons do not need to wear N95 Masks; they may wear regular masks. This has come up at a few IRBs due to the slightly confusing FDA Approval Letter. Please let us know if you run into this issue; we can help to provide language/justification for your IRB. • Pre-op or prophylactic IV antibiotics are permissible (tracked on CRFs) • Post-op IV or PO antibiotics are permissible • Patient may be discharged on antibiotics

19. Surgeon “Quick Facts” • Barb Steverson in Tampa put together a great one-pager “Quick Facts” to provide to all of the surgeons at her site that may be involved in the VANCO study • We will post this to the METRC website along with the Surgeon Training recording in case other sites want to download and use it • Similarly… if you have developed any resources at your site that you would like to share… please send them our way!

20. Follow-up Data Collection • Participants will return for follow-up visits at 2 weeks, 3 months, and 6 months following date of definitive fixation surgery (time 0) • We’ve updated the Follow-up Visit Windows spreadsheet on the METRC website to include the VANCO follow-up visits • The REDCap calendar tool and monthly report queries will use the number of days specified in this table to calculate visit windows • Clinical Assessments: Diagnosis of infection and detailed assessment of evidence of infection, Complications • Patient reported outcomes at 6 months

21. Event Reporting • Adverse Events: As with all METRC studies, these are reported standardly on our data collection forms via infection and complications tables • Serious Adverse Events (CRF16): (1) Unexpected, AND (2) related or possibly related to study participation, AND (3) serious defined as severe, life-threatening, or death • Because this is an FDA study of an off-label use of vancomycin, there are a few complications which should always be reported as Serious Adverse Events: (1) New diagnosis of renal failure, and (2) severe allergic reaction to vancomycin such as anaphylaxis or a severe local reaction • The CRFs include prompts/reminders to report these events should your patients experience them while participating in this study • If a reported SAE is determined to be related to study participation, the MCC will inform all participating sites ASAP. The MCC will also inform the FDA. • We will need the sites’ help, however, in completing the FDA Form 3500, which documents the events

22. Other Reporting • Out of Window or Missed Follow-up Visits (AF03) • Monthly report queries will help remind you to complete these forms • Patient Final Status (AF01) • Complete when a patient completes the study or is discontinued early • Protocol Deviations (AF05) • We have to be vigilant about recording these for FDA reporting purposes • We’ve included prompts throughout the CRFs • When in doubt, complete a PD form • Unanticipated Problems (AF04) • This form should be used to document instances of breaches of patient confidentiality

23. Implementation Questions • Screening & Enrollment processes • How will you ensure that you capture all eligible patients? • Follow-up Plans • How will you keep in contact with study participants and ensure that you capture all follow-up visits? • How will you know what follow-up visits are upcoming? • Data Collection/ Data Entry • How will you ensure that all data is captured and entered in a timely fashion? • How will you obtain data that is not standardly found in the medical record? (more on this later) • How will you obtain AIS codes? • How will you ensure that the labels from the vials of vanco powder are retained? • Study Team Communication • Where, when, and how often will you have the opportunity to meet with the Study PI? • How will you get your questions answered, or get help from the Study PI in between meetings? • Coverage Plans • Who will provide coverage for the study team should someone be absent? • Patient stipends • How will you pay patients their $50 honorarium at the 6 month visit? These are the plans and processes that you should iron out with your study team before you enroll your first patient! The MCC team is also here to help you think these things through.

24. Vanco Stocking and Dispensing • Some sites will need to stock and dispense the vanco for study purposes. These sites will need to make sure they can answer these questions before enrolling their 1st patient: • How is the vanco ordered? • How/where will it be stored? • How will the vial of vanco get dispensed to the OR in time for the definitive fixation procedure? • Remember that the patient should not be charged for the study drug!

25. Monitoring • Monthly Data Quality Reports • After we start enrolling more patients, we will distribute monthly data quality reports • Reports will be distributed within the first 10 days of the month. Replies/resolutions should be submitted to the MCC by the due dates specified, usually the final week of the month. • Please try to stay on top of these queries! They are a useful communication tool between sites and the MCC study team. • CRF Audits • After you enroll your 1st two patients, we will ask you to send us copies of all of their baseline CRFs • We will review them to ensure that you’re responding to all necessary items appropriately, that errors are corrected in accordance with GCP, and that the data on the CRFs matches the data entered into REDCap • If numerous issues are identified, we will work closely to re-train your team on completing the CRFs and may request that you send CRFs for additional patients • On-Site Monitoring Visits/ Remote Monitoring Visits • On-site monitoring for this study will be conducted in conjunction with monitoring for other METRC studies per the Monitoring SOP • The focus of visits will be source document verification • Pilot: We are planning to provide checklists/scripts for surgeons to use in dictation to ensure that all VANCO clinical data is source verifiable

26. Surgeon Checklists/Dictation Templates • It has always been a goal in METRC to create materials, checklists or dictation templates, for surgeons to use to ensure that 100% of our clinical data is source verifiable • Because of the additional layer of oversight due to the FDA IND, we believe that VANCO is an appropriate study to implement this practice • To start: We will have a checklist and/or dictation guidance sheet to cover most information recorded on Study Injury Characteristics Form (CRF05) and Definitive Fixation Form (CRF07) • Calling all volunteers! We’d like to get the draft materials out to a handful of sites for input from coordinators and surgeons. Please let us know if you would be interested in participating in this process. We also plan to reach out to sites directly to make sure that we have enough representation from participating sites. • The goal is to finalize the materials by the end of February in time for the first cluster of sites to begin screening and enrollment.

27. Invoicing • Invoices will be generated on a quarterly basis by the MCC • Based on data in REDCap; any entered data point “counts” as a completed event (baseline or follow-up visit) • $1,100 total per patient enrolled • $500 for baseline • $600 at final follow-up, prorated for any missed follow-up visits (i.e., $200 less for any missed visit) • Invoices sent by Cathy Epstein. Sign and return them ASAP upon receipt to ensure quick payment

28. Discussion and Q&A