Optimizing Orthopedic Pain Management: PAIN Study Overview

1. Improving Pain Management and Long Term Outcomes Following High Energy Orthopedic Trauma (PAIN Study) Research Coordinator Training PIs: Renan Castillo, PhD Srinivasa N. Raja , MD J. Lawrence Marsh, MD

2. Introductions

3. Agenda • Study Introduction • Background and study rationale • Study Aims • Study Outcomes • Inclusion/Exclusion criteria • Enrollment and Study Flow • Patient Screening • Patient Enrollment • Data Collection • Monitoring • Regulatory Process • IRB Submission • Certification • Research Pharmacies and Invoicing • Study Contacts • Timeline

4. Study Introduction

5. Background Main Pain Study • Pain is a common consequence of orthopaedic trauma • Poor pain control predicts physical disability, delayed return to work, psychological distress, low satisfaction with healthcare, and failure to participate in physical therapy • 50% to 70% patients experience moderate/severe pain in acute care settings and report insufficient postoperative pain relief • Inadequate pain management can prolong patient recovery, increasing length of hospital stay and health-care costs • 30-50% of patients who have acute postoperative pain develop chronic pain that can have major negative effects on quality of life

6. Background PTOA Pilot Study • A subset of patients who experience orthopedic trauma go on to develop chronic pain in the form of post-traumatic osteoarthritis (PTOA) • PTOA is a disabling condition that results from joint injury • PTOA is a serious health condition that often leads to substantial pain, disability, loss of work and decreased general health status

7. Rationale Main Pain Study • Preoperative and perioperative pain management has been found to substantially improve post surgical pain control in numerous settings • These techniques have not been widely used in orthopaedics due to conflicting data about increased risk of nonunion, wound closure and bleeding complications • Given the central role of pain management in the etiology of long-term disability following trauma, it is critical to definitively resolve this question in the context of a randomized clinical trial

8. Rationale PTOA Pilot Study • There are knowledge gaps in the understanding of the development of PTOA • The University of Iowa Center of Research Translation (UI CORT) has developed novel techniques which use radiographs and CT images to objectively quantify the mechanical factors (fracture severity and contact stress challenge) which may help to explain the pathogenesis of PTOA

9. Specific Aims Main Pain Study Specific Aim 1: Evaluate the effect of standard pain management (Group 1) vs. standard pain management plus pre and peri-operative NSAIDs (Group 2) in the treatment of severe lower limb fractures Specific Aim 2:Evaluate the effect of standard pain management (Group 1) vs. standard pain management plus pre and peri-operative pregabalin (Lyrica) (Group 3) in the treatment of severe lower limb fractures Specific Aim 3: Estimate the incremental cost effectiveness of each adjunctive analgesic therapy relative to standard of care analgesic therapy in the treatment of severe lower limb fractures

10. Specific Aims PTOA Pilot Study PTOA Specific Aim 1: Measure the incidence of PTOA and chronic pain for up to 24 months following fracture reduction surgery PTOA Specific Aim 2: Quantify the extent to which fracture severity and post-reduction contact stress are related to the development of PTOA

11. Primary Outcomes • Opioid Utilization: Morphine equivalent opioid utilization during initial hospitalization through 48 hours following definitive fixation • Persistent Pain: Patient reported persistent pain measured at 3, 6 and 12 months following hospital discharge using the Brief Pain Inventory (BPI) and an additional battery of questions to assess neuropathic pain (painDETECT) • Surgery for non-union: Defined as non-prophylactic surgery for nonunion performed between six months and a year following initial hospital discharge

12. Secondary Outcomes • Pre Surgical Pain Intensity • Post Surgical Pain Intensity • Length of Index Hospitalization • Adverse Effects/Complications • Functional Outcome • General Health Status (VR-12) • Presence of Depressive Symptoms (PHQ-9) • PTSD Risk • Medical Costs • Fracture Severity (CT scan and Radiographs) • Development of PTOA

13. Main Inclusion Criteria • Patients with isolated, unilateral, Grade I &II open or closed pilon (distal tibial plafond) or calcaneus fractures requiring operative treatment with fixation • Patients 18-80 years old inclusive • Patients who are English or Spanish competent • Treating physicians agree that none of the study drugs are indicated for standard of care treatment for this patient • Patients able to be followed at the METRC facility for at least 12 months following definitive surgical procedure

14. Exclusion Criteria • Patients unable to provide informed consent • Patients with difficult follow up • Patients with medical contraindications to using study drugs (including allergies) • Patients with other orthopedic or non-orthopedic injuries requiring operative intervention • Patients with current prescription drug use or IVDA • Transfer patients who are >48 hours post injury • Patients who are expected to have a post-surgical stay less than 24 hours. • Patients with head injuries • Patient speaks neither English nor Spanish • Patients who are pregnant or lactating at time of screening *See protocol for detailed list of exclusion criteria

15. Enrollment and study flow

16. PTOA Protocol <48 hrs post injury Consent, Randomization, Baseline Interview SOC pain management + Oral Therapy according to randomization for up to 14 days; Pain assessment q 12 hours via pain log Preceding definitive fixation; Patient may be at hospital or at home IF SOC: CT Scan Perioperative Perioperative IV/Oral Protocol, According to Randomization 48 Hrs post-op Postoperative Assess pain, abstract opioid use from records, monitor AEs; Oral Therapy ends. 2wks - 3 m post-op IF SOC: CT Scan NOT SOC: CT for selected cases; paid by study 6 m post-op BPI/Neuropathic pain msmt, SMFA, SF12 IF SOC: Radiographs 12 m post-op BPI/Neuropathic pain msmt, SMFA, SF12, PHQ, PCL, AOS IF SOC: Radiographs 18 m or 24 m post-operative IF SOC, Radiograph AOS RADIOGRAPHS for pts with previous study CTs, paid by study Pain Protocol

17. Patient Screening • Approximately 495 patients will be enrolled over a 6 month period • The following patients should be screened for the Pain study, and thus have a completed CRF00: all patients between the ages of 18 and 80 (inclusive) with isolated, unilateral, Grade I & II open or closed pilon (distal tibial plafond) or calcaneus fracture that requires operative treatment with fixation • CRF00 should be completed and entered into REDCap for all screened patients

18. Patient Enrollment • Within 48 hours after injury patients will: • Patients will be consented and randomized - NO LARS! • Start on a study medication arm • Attending surgeon and research coordinator will be involved with consenting the patient • Patients may be discharged home before definitive fixation. Note: this may be less than 48 hours post-injury. Provided consent is obtained and study medications initiated, these patients would still be eligible, and would be discharged with instructions to take study medication as directed. • If allowed by local IRB, patients can be enrolled in other observational METRC or non-METRC observational studies

19. Study Procedures • Initiating medication in hospital – dispensing meds, abstract med administration, pain scores and AEs from chart • Patient takes meds at home, continues to document taking meds, as well as pain/AEs on blister pack log • Return to hospital – treatment surrounding operative procedures; abstract med administration, pain scores and AEs from chart IV; patient does not get blister pack meds during that time

20. Exclude Open Grade III Fracture Screen High Energy Orthopedic Trauma to Ankle Medication Dosing Injury-48 hours Closed or Open Grade I/II Enroll within 48 hours and Randomize to Treatment Group + SOC Therapy 48 hours – definitive fixation; may include intermediate operative procedure Group A: Placebo Group B: NSAID Group C: Gabapentinoid Oral Placebo; up to 2 wks Oral NSAID (Meloxicam 7.5 mg po bid); up to 2 wks Oral Gabapentinoid (Pregabalin 75 mg po bid); up to 2 weeks If the patient experiences a surgical procedure prior to the definitive fixation (e.g. calcaneal fracture repair, or fibular and/or spanning external fixation), suspend oral therapy and initiate perioperative adjunctive analgesic therapy; otherwise PO therapy for up to 2 weeks, or through definitive fixation Oral Placebo + IV Placebo Therapy until resumption of oral placebo Oral Placebo + 30 mg IV ketorolac 1 hour prior to surgery and q6h post procedure until resumption of oral NSAID Therapy IV Placebo + 300 mg pregabalin po prior to surgery and 75 mg po bid post procedure until definitive fixation. Definitive Fixation Definitive fixation – 48 hours post op Oral Placebo + IV Placebo Therapy Oral Placebo + 30 mg IV ketorolac 1 hour prior to surgery and q6h for 48 hs post procedure IV Placebo + 300 mg pregabalin PO prior to surgery and 75 mg PO bid post procedure for 48 hrs

21. Data Collection Main Pain Study • In-hospital data collection • Baseline interview • Index hospitalization (opioid utilization, concomitant medications, administration of study medications, pain scores, complications, lab results) • Multidimensional Post Surgical Pain Scale • Follow up data collection • 3 months—Brief Pain Inventory + pain DETECT, clinical follow-up • 6 months—Short Musculoskeletal Function Assessment (SMFA), Veterans RAND (VR-12), Brief Pain Inventory + pain DETECT, clinical follow-up • 12 months—SMFA, VR-12, Patient Health Questionnaire, PTSD Checklist, Brief Pain Inventory + pain DETECT, clinical follow-up • Up to 24 months (PTOA)—CT scan, Radiographs, Ankle Osteoarthritis Scale

22. Assessing for Complications Common adverse effects and complications will be assessed through patient report on blister pack log or abstraction of medical record through definitive fixation (and 48 hours following definitive fixation) Self-reported by the patient • Somnolence • Dizziness • Headaches • Other central nervous system effects • Peripheral edema • Visual changes • Dry mouth Clinical survey • Excessive bleeding • Thrombocytopenia • Anemia *Assessed during the index hospitalization and at discharge from additional surgical admissions up to definitive fixation.

23. Assessing for Complications Complications will be assessed through patient report and clinical assessment at all follow-up visits Self-reported by the patient • Pain • Opioid utilization • Other pain medications Clinical survey • Rehospitalizations (non-union, infection, other) *Assessed at scheduled follow-up visits, or any other unscheduled clinic visit.

24. Regulatory process

25. IRB Procedures • This protocol has been approved by the JHSPH IRB • Submit master protocol to local IRB within two weeks after the distribution of materials (Training WebEx) • Includes required DoD reporting language • Includes consent form with required DoD language • HIPAA form, site specific, must include required DoD language • Submit IRB approved documents (IRB application, protocol, consent form, HIPAA form to DoD within one week of receiving IRB approval • Must include PI biosketch/CV, description of roles and responsibilities, human subjects training certification (PI, coPI, AI), and conflict of interest statements for PI and AIs if appropriate (see DoD checklist)

26. Documents for SubmissionNote: all attachments included in protocol

27. Anticipated Amendments • Recruitment video and flipchart • Spanish versions of recruitment materials and interviews to come.

28. Questions? • Bulletin Board on the METRC website will list IRB FAQs and provide an area for Research Coordinators to communicate with each other and post study related questions • You can subscribe to the Pain study board to receive notice of any new posts

29. Certification Procedures • Use MCC Certification checklist as guideline for submitting materials for this process. • Complete certification forms and submit electronically to the MCC Study Manager. • Training • IRB approval • REDCap access • All investigators participating in the Pain study and named on IRB application must be certified, in addition to the research coordinator. • MCC Manager will review Clinical Site Certification documents for completeness and correctness within one week of receipt • A complete Clinical Site Certification packet will be certified within two business days of receipt • Sites must receive approval from MCC before patient enrollment can begin

30. Research Pharmacy (RP) • Need to establish a contract between METRC and your RP. METRC will manage this process and keep you informed • RP will ONLY be responsible for dispensing medications. Medications will be sent to the pharmacy pre-packaged, blinded, and ready to administer • METRC will pay for all research-related costs that originate in the RP • We will ask you to help facilitate the introduction to the RP

31. Invoicing • Core sites will be paid up to $1,000 for each patient enrolled. This sum is independent of RP costs • On a quarterly basis the METRC Coordinating Center (MCC) will run an enrollment report from the REDCap system for each site • The MCC will send the report to the site for signature and verification • The site  will be required to sign this 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 • There is a designated budget to cover all research pharmacy fees, which will be delivered through a modification to the site subcontract

32. Study Materials • Protocol + all associated attachments • CRF Binders (for each patient) • CRF Guidance Document • Patient Enrollment Materials (English & Spanish) • Brochures • To be developed: Flip chart and video • Drugs will be delivered to research pharmacies by Fisher. Blister packs will have patient pain/AE log incorporated into packaging

33. Study Contacts • For questions about eligibility: • Renan Castillo, PhD: prefer email because of need to adjudicate between surgical or pain specialist (rcastillo@jhsph.edu), but can call/text 443-804-1748 • For technical (REDCap) assistance: tech@metrc.org • For questions related to all other study procedures: • Post questions to METRC Bulletin Board • If you have questions specific to your site, contact the MCC Study Manager • Tara Taylor, tjtaylor@jhsph.edu

34. Next Steps Submit to your IRB! Contact your research pharmacy

35. Discussion