A Multi Center Prospective Observational Study of Nerve Repair and Reconstruction

1. A Multi Center Prospective Observational Study of Nerve Repair and Reconstruction Associated with Major Extremity Trauma (NERVE study) IRB Prep Training: March 9, 2016 PI: Jaimie Shores(Johns Hopkins University) Co-PI: Glenn Gaston (OrthoCarolina)

2. Agenda • Study Team Introductions • Overview of the Study • Regulatory Process • IRB Submission • Certification • Invoicing • Study Materials • Timeline

3. Introductions

4. Protocol Committee Jaimie Shores (Study PI) Ellen MacKenzie, PhD Johns Hopkins University Johns Hopkins Bloomberg School of Public Health Glenn Gaston (Study Co-PI) Daniel Scharfstein, ScD Carolinas Medical Center Johns Hopkins Bloomberg School of Public Health Donald Lee, MD Lisa Reider, PhD Vanderbilt Johns Hopkins Bloomberg School of Public Health Ray Pensy, MD Elizabeth Wysocki University of Maryland Johns Hopkins Bloomberg School of Public Health Thomas Lehman, MD University of Oklahoma Zhongyu Li, MD Wake Forest Wade Gordon, MD Walter Reed National Military Medical Center

5. Background • Incidence and impact of peripheral nerve injury (PNI) not well understood in civilian or military populations. • Treatment of PNI is based on expert opinion; no evidence based guidelines • METRC established a nerve injury registry to better understand the types of injuries and their treatments across multiple trauma centers

6. Nerve Injury Registry • 15 METRC sites participated • Patients 18 years or older • Prospective collection of all nerve injuries associated with extremity trauma admitted to the site hospital (though most were through ortho) • Data collected over a 6 month period • Single sheet data collection performed during their initial hospitalization only

7. What we learned • Type of treatment (non-operative vs. use of primary repair, wraps, tubes, transfers and grafting vs. nerve exploration) varied across centers and by nerve location and injury mechanism • Large numbers of patients with major peripheral nerve injuries (338 injuries entered into the registry) can be captured in a short period of time across multiple METRC sites. • Data from the registry was the basis for the current prospective observational study funded by the DoD PRORP to address important treatment questions.

8. Overall Objective To capture data on the treatment and outcomes of upper extremity PNI in order to formulate treatment algorithms to test in future trials.

9. Primary Study Aim Specific Aim #1: To characterize the incidence, type and treatment of PNI resulting from upper extremity trauma admitted to US military and civilian trauma centers. Hypothesis:There will be substantial variation in treatment of PNI and that choice of treatment will be associated with surgeon training and specialization as well as center characteristics.

10. Secondary Study Aim Specific Aim #2: To characterize the association between treatment (timing and approach) and outcomes. Hypothesis 2a: Patients with immediate repair/reconstruction will have earlier and more complete motor/ sensory recovery than those who obtain surgical repair/reconstruction after initial non-operative treatment. Hypothesis 2b. Patients treated with nerve transfer, autograft or allograft will have better sensory/motor function by 24 months post injury than those treated with primary repair, nerve tube reconstruction, or initial non-operative treatment converted to any operative treatment. Hypothesis 2c: Patients treated with nerve transfer, autograft or allograft will have earlier return to duty or work than patients treated with primary repair, nerve tube reconstructions, or initial non-operative treatment converted to any operative treatment. Hypothesis 2d: Patients treated with nerve transfer, autograft or allograft will experience less pain at each time point than patients with nerve injuries treated using primary repair, nerve tube reconstruction, or initial non-operative treatment converted to any operative treatment.

11. Outcome Measures • Surgical complications including surgical site infections, wound dehiscence/breakdown, exposure of nerves and/or their repairs and reconstructions, breakdown of nerve repair and reconstruction, seroma/hematoma, and other local wound complications. • Pain using the Brief Pain Inventory (BPI). • Sensory and motor function using the British Medical Research Council (BMRC) tool. • Global hand function using measures of grip strength and range of motion. • Disability using the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH). • Depression and PTSD using the Patient Health Questionnaire (PHQ-9) and the standard PTSD Checklist (PCL) • Return to work or duty using standard questions used in other METRC studies and the Work Productivity and Activity Impairment (WPAI) questionnaire.

12. Inclusion Criteria • Ages 18-54 • Sustained a peripheral nerve injury (including iatrogenic injuries and partial nerve injuries) resulting from upper extremity trauma meeting the following criteria: • Involves injury or dysfunction to motor, or motor and sensory function of the axillary, radial, median, ulnar, or musculocutaneous nerve with injury localized distal to the brachial plexus cord level and proximal to the distal flexion crease of the wrist • Involves a "mixed" nerve segment (i.e. involves a location of any of the above specified nerves that can be expected to have both sensory and motor axons present) but does not include sensory only distal terminations of the same nerves. • Nerve injury diagnosed within 30 days of the initial upper extremity trauma

13. Exclusion Criteria • Closed injuries that do not undergo surgical exploration within 30 days of injury • Injuries to the brachial plexus roots, trunks, divisions and cords • Injuries to the nerves distal to the distal flexion crease of the wrist • Injuries that involve a distal extension of the parent nerve that is considered sensory only (superficial radial nerve, lateral ante brachial cutaneous nerve, etc) • Previous motor or sensory deficit prior to injury (e.g. resulting from trauma, stroke, muscular, neurologic, neuromuscular disorder, etc.) • Documented psychiatric disorder that limits ability to consent and maintain follow-up • Unable to speak either English or Spanish • Severe problems with maintaining follow up (e.g patients who are prisoners or homeless at time of injury or who are intellectually challenged without adequate family support).

14. Study Overview Sample size: 450 patients with upper extremity PNI (We are enrolling all patients with a PNI diagnosis; not just those patients who receive surgical treatment) # of study sites: 13 METRC civilian centers & 2 MTFs (initial site selection based on registry participation and volume) Duration: 4 years total; 6 month development period; 18 month enrollment period; 24 month follow-up.

15. Study Overview Hospitalization for initial injury Clinic Visits Referrals Upper Extremity PNI Diagnosis Obtain Consent Baseline Data Collection 3 mos Clinical Assessment Patient Interview 6 mos Clinical Assessment Patient Interview 12 mos Clinical Assessment Patient Interview 18 mos Clinical Assessment Patient Interview 24 mos Clinical Assessment Patient Interview

16. Patient Screening & Enrollment • Our goal is to enroll 450 patients over an 18 month period. • All patients between the ages of 18 and 54 (inclusive) admitted to the hospital or returning to clinic with an upper extremity injury with motor or sensory loss will be screened for eligibility. • Identifying all eligible patients may be a tricky since they can be identified at several points along the care continuum (i.e. in hospital for treatment of arm injury; at clinic after discharge). • We are enrolling all patients with a PNI diagnosis; not just those patients who receive surgical treatment. • No LAR consent permitted; patients must be able to respond to the baseline sensory and motor assessments. • If allowed by local IRB, patients can be enrolled in another METRC or non-METRC study.

17. Baseline Data Collection • Characteristics of the patients (demographics; pre-injury function and health; other injuries) • General injury characteristics and details about the initial hospitalization • Characteristics of PNI (mechanism, nerve type and location, length of injury or gap) • Initial Treatment (non-operative; exploratory; or operative treatment including details about the types of procedures performed) • Characteristics of the treating surgeon • Baseline assessment of sensory and motor function, range of motion and hand strength.

18. Follow-up Data Collection Clinical Assessment • Treatment performed since the last visit • Complications • Pain medication use • Assessment of sensory and motor function, range of motion and hand strength. Patient Interview • Return to usual activities & general health status Self Administered Surveys • Disability (DASH) • Pain (BPI) • Depression (PHQ-9) • PTSD (PCL)

19. Regulatory process

20. IRB Procedures • Submit master protocol to local IRB • Includes required DoD language • Includes consent form with required DoD language • HIPAA form must include required DoD language • Submit to local IRB by Monday, March 21st and Liz know once it’s been submitted. • Submit IRB approved documents (Local IRB application, protocol, consent form, HIPAA form) to DoD HRPO for review and approval • Must include PI Biosketch or CV, Roles & Responsibilities Table, and Human Subjects Training Certificates for PI and AI’s, (see DoD Email Templates and Checklists posted to the website) • Submit to DoD within 7 days of receiving local IRB approval and remember to copy Study Manager on your submission emails

21. Documents for Submission

22. Documents Pending We are creating a study brochure for you to give to patients that summarizes the study. This will be posted to the METRC website when it becomes available (we will email you to let you know).

23. Reporting Requirements

24. Certification Procedures • Use MCC Certification email templates and checklist as a guide for submitting materials for this process • Submit electronically to the MCC Study Manager within 7 days of DoD submission • Clinical Site Certification Form • Medical Licenses (if not previously submitted or expired) • Biosketch or CVs (if not previously submitted) • Good Clinical Practice Training Certificates (for PI and RC, if not previously submitted or expired) • Must receive approval from MCC before patient enrollment can begin

25. Invoicing • Each site will receive $5,000 in start-up money and $2,000 per patient enrolled (this includes $150 for patient honoraria). • Based on registry numbers, we estimate that on average, each civilian site will enroll a total of 36 patients over the 18 month enrollment period. • The METRC Coordinating Center (MCC) will run quarterly invoice reports based on data entered into REDCap for each site.  • The invoice report will be sent to the site for signature and verification.  • The site  will be required to sign this invoice report and send it back to the MCC as a PDF document via email or through the mail.  • Once the signed document is received by the MCC it will be processed for payment.

26. Study Materials & Resources • CRF Binders (for each patient) & supplemental instructions will be posted to the website. • Screening app available for download on your smart phone or computer • Study Brochure • Tools for sensory assessments (2 point discriminators; monofilament kits; dynamometers, strength gauge) • SOPs for sensory and arm function assessments (will be posted on the website)

27. Timeline and Next Steps • Submit study materials to your local IRB by 3/21/2016 • Submit IRB approved documents to the DoD HRPO (follow the checklists and use the templates; call us for help) • Training on the study procedures and data collection will be given in late April.

28. Discussion