PARITY Launch Meeting September 28 th , 2012 Toronto, ON, Canada

1. A Multi-Center Randomized Controlled Study Comparing Alternative Antibiotic Regimens in Patients Undergoing Tumor Resections with Endoprosthetic Replacements PARITY Launch Meeting September 28th, 2012 Toronto, ON, Canada Breakout Session for Research Staff

2. Agenda • Study Overview • Screening Patients & Obtaining Consent • Randomization • Case Report Forms (CRFs) Overview • iDataFax Overview • Break • CRF Completion Guidelines • Submitting Adjudication Materials • Study Timelines • Ready, Set, Go!

3. Study Overview

4. Current Funding • Orthopaedic Research & Education Foundation: • OREF/MSTS Clinical Research Grant in Orthopaedic Oncology • Physicians’ Services Incorporated Foundation (Ontario, Canada) • Private Donation: We would like to thank the Dacol-Manherz family for their generous donation to the PARITY study

5. Tumor Surgery • Primary bone tumor of the lower extremity • Wide resection • Endoprosthetic Replacement

6. The Need for the PARITY Study • Extremely HIGH infection rates • No guidelines for Antibiotic Prophylaxis in Tumor Surgery • In General Arthroplasty: • Single pre-operative dose of antibiotics • Antibiotics discontinued within 24 hours of surgery • Survey shows that antibiotic use varies among Orthopaedic Oncologists (Hasan et al., 2012)

7. Primary Objective Are 5 days of postoperative antibiotics more effective at decreasing the rate of infection when compared to 24 hours of postoperative antibiotics?

8. Secondary Objectives What is the impact of the postoperative antibiotic regimen (24 hours vs. 5 days) on the development of antibiotic-related complications (i.e. gastrointestinal infections, fungal infections, etc.)? What is the impact on the rate of re-operations? What is the impact on patient functional outcome after one year?

9. Primary Outcome • Rates of deep post-operative infections in each of the study arms. Infection will be defined using the Centers for Disease Control (CDC) definition of deep surgical site infection. • Infection will be adjudicated by an independent and blinded adjudication committee.

10. Secondary Outcomes • Antibiotic-related adverse events • Rate of re-operations • Patient function • Musculoskeletal Tumor Society Functional Score (MSTS) – clinician administered • Toronto Extremity Salvage Score (TESS) – patient administered

11. Antibiotic Regimens • Pre-op: 2g cefazolin 60 minsprior to the of the procedure • Intra-op: 2g cefazolin every 3-4 hours during procedure (standard) • Post-op: 24 hours cefazolin (2g) followed by 4 days saline (short) • OR • 5 days cefazolin (2g)(long)

12. Blinding • All antibiotic bags will be identically shrouded • Patients, surgeons, nurses, research staff, data analysts and the Central Adjudication Committee will be blinded • Only the pharmacy technician who randomizes the patient and prepares the shrouded antibiotic bags will not be blinded

13. PARITY Trial Organization STEERING COMMITTEE Overall responsibility for the trial DATA MONITORING COMMITTEE Review of adverse events and stopping rules based on benefit and harm CENTRAL ADJUDICATION COMMITTEE Review and classification of all clinical events METHODS AND COORDINATING CENTRE Data management, daily conduct of the trial PARTICIPATING CLINICAL CENTRES Patient recruitment and follow-up as per study protocol Trial Organization

14. Inclusion Criteria • Men and women 15 years of age or older • Primary bone malignancies or benign aggressive tumors of the lower extremity • Reconstruction with tumor prosthesis planned Treatment by excision and endoprosthetic reconstruction • Provision of informed consent

15. Exclusion Criteria • Current known Methicillin-resistant Staphylococcus Aureus (MRSA), or Vancomycin Resistant Enterococcus (VRE) colonization • Documented anaphylaxis or angioedema to penicillin or study antibiotics [Ancef® (cefazolin)] • Reconstruction to include allograft • Prior surgery within the surgical field (excluding a biopsy) • Prior infection within the surgical field • Current known immunologically-deficient disease conditions (excluding chemotherapy) • Known renal insufficiency with estimated eGRF 54 mL/min • Skeletal Immaturity • Upper extremity tumor

16. Trial Conduct Procedure Patient Recruitment, Randomization and Surgical Interventions Identification of Patients Direct referral-within center Data Collected Assessment of Study explanation Patient EligibilityHistory-review eligibility criteria, Screening Form and other relevant medical conditions Physical Examination Radiographs Informed Consent, if eligible Informed Consent MSTS, TESS (baseline) All eligible patients who consent to the trial Randomization24 hour web-based system Baseline Form Key patient information recorded Randomization FormRandomization assigned SurgeryEither short or long arm Surgical Form Surgical protocols will be followed

17. Trial Conduct Procedure Follow Up Schedule 2 Weeks Assessment of outcome events Follow-Up Forms 6Weeks Assessment of outcome events Follow-Up Forms 3 Months Assessment of outcome events Follow-Up Forms MSTS, TESS 6 Months Assessment of outcome events Follow-Up Forms MSTS, TESS 9 Months Assessment of outcome events Follow-Up Forms 12 MonthsAssessment of outcome events Follow-Up Forms MSTS, TESS *Follow Up Forms include AEs, SAEs, infections, re-operations, protocol deviations or wound healing problems, and other appropriate forms.

18. Trial Conduct Procedure Patient Recruitment, Randomization and Surgical Interventions Identification of Patients Direct referral-within center Data Collected Assessment of Study explanation Patient EligibilityHistory-review eligibility criteria, Screening Form and other relevant medical conditions Physical Examination Radiographs Informed Consent, if eligible Informed Consent MSTS, TESS (baseline) All eligible patients who consent to the trial Randomization24 hour web-based or telephone Baseline Form Eligibility criteria reviewed again Randomization Form Key patient information recorded Randomization assigned SurgeryEither short or long arm Surgical Form Surgical protocols will be followed

19. Screening Patients and Obtaining Informed Consent

20. Patient Screening • It is VERY IMPORTANT that ALL patients with a primary bone tumor of the lower extremity are screened! • Classify patients as: • Included • Excluded • Missed • Complete Screening Form 1.1

21. Patient Study ID • Included Patients • IDs start at 1001 (assigned by site research staff) • Missed Patients • IDs start at 2001 (assigned by site research staff) • Excluded Patients • IDs start at 3001 (assigned by site research staff)

22. Obtaining Informed Consent • Research staff meets with the patient to discuss the trial and review the Information Sheet/Consent Form • Patient reads the Information Sheet/Consent Form • Research staff ask the patient to describe the key aspects of the study in their own words • Research staff explains the requirements for follow-up visits and completing questionnaires • Signature of consent form by patient and research staff (copy provided to patient) • *If the patient is unable to give informed consent, the legally authorized representative will be approached by the research staff and the same process will be followed

23. Randomization

24. Trial Conduct Procedure Patient Recruitment, Randomization and Surgical Interventions Identification of Patients Direct referral-within center Data Collected Assessment of Study explanation Patient EligibilityHistory-review eligibility criteria, Screening Form and other relevant medical conditions Physical Examination Radiographs Informed Consent, if eligible Informed Consent MSTS, TESS (baseline) All eligible patients who consent to the trial Randomization24 hour web-based system Baseline Form Key patient information recorded Randomization FormRandomization issued to patient SurgeryEither short or long arm Surgical Form Surgical protocols will be followed

25. Before Randomization • Obtain Informed Consent • Complete Baseline Characteristics Forms • Complete Tumor Characteristics Forms • Complete • MSTS (physician completes) • TESS (patient completes) • Complete top half of the Randomization Form

26. Randomization WHO Pharmacy Team Member at each site WHAT Randomize patients to short arm (24 hours) or long arm (5 days) WHEN At or near incision time; before surgery completed WHERE Online randomization system (www.randomize.net) WHY To minimize bias

27. Randomization is a Team Effort! The pharmacist will randomize the patient but only after the site research staff provides them with the required information.

28. Before Randomizing a Patient, the Site Coordinator Must: • Apply inclusion and exclusion criteria to the patient • Obtain signed patient consent or proxy • Have agreement to randomize from the surgeon/resident/fellow

29. Before Randomizing a Patient, the Pharmacist Must: • Know the site’s username and password for www.randomize.net • Receive from the site research staff the partially completed Randomization Form which includes the patient’s date of birth, the patient’s tumor location (femur or tibia) and the patient’s ID • Have a pen to record the treatment allocation

30. www.randomize.net

31. Troubleshooting Randomization If you run into any problems randomizing a patient you can call randomize.net at (613) 366-4796 or email them at info@randomize.net.

32. Case Report Forms (CRFs)Overview

33. Completing CRFs

34. CRF Corrections  Do NOT make corrections this way  Show original answers, initial & date all changes

35. Submitting CRFs • Before submitting, check CRFs for accuracy, completeness, and legibility • The most efficient and preferred method of submitting case report forms to the PARITY Methods Centre is by Electronic Data Capture (EDC), via the secure iDataFax website • Scanned CRFs, saved in PDF format, can be sent to iDataFax using DFSend – a program that comes with iDataFax.

36. iDataFax Overview

37. What is iDataFax? • A direct computer data management system for collecting study CRFs, including: • Intelligent Character Recognition • Automated Quality Control (QC) report system • Increased speed & efficiency of data collection • Improved data quality through continuous monitoring & QC reports METHODS CENTER

38. Quality Control Reports • QC Reports run every two weeks • Sent out by email to each site • Identifies and lists all items in the CRFs which are incomplete, unclear, illegible, or missing • Respond by entering the corrections to the ORIGINAL CRF in iDataFax or by resending the corrected page as a PDF file through DFSend • Initial and date all changes (iDataFax does this automatically)

39. Quality Control (QC) Reports

40. Agenda • Study Overview • Screening Patients & Obtaining Consent • Randomization • CRF Overview • iDataFax Overview • Break • CRF Completion Guidelines • Submitting Adjudication Materials • Study Timelines • Ready, Set, Go!

41. CRF Completion Guidelines

42. Patient Contact Form (L-1 and L-2) • Do NOT forward this to the Methods Centre • Additional contacts who do NOT live with the patient • US Sites: Release of Records HIPAA Authorization required to request records from primary care physician

43. Randomization Form (2.1) • Questions 1 – 3: completed by RC • Questions 4 – 5: completed by Pharmacist/Technician • Pharmacist to submit completed form to the Methods Centre within 1 business day of patient randomization & file separate from all other patient data

44. Attending Surgeons (3.1) • List surgeon names • Indicate level of expertise: • Number of cases performed in the last year • Number of cases performed over entire career

45. Baseline Characteristics Form (4.1 – 4.3) • Ethnicity • Location of Tumor • Other known malignancies or metastases • History details • Patient medication • Preoperative treatment modalities (chemo and/or radiation) • Mode of delivery

46. Tumor Characteristic Form (5.1) • Type of tumor • Type of biopsy performed • Indicate if soft tissue mass exits, its dimensions & location • If positive, specify organism • Indicate if there is skin, muscle, and/or vascular involvement

47. Surgical Report Forms (6.1 – 6.3) • Captures all surgery details including: • Operative time • Type of sterilization • Length of incision • Amount of skin/muscle excised • Length of bone resected • Prosthesis type

48. Surgical Pathology Report Form (7.1) • To be completed following surgery, once diagnosis finalized • Name of pathologist • Tumor pathology and subtype, if any (i.e., fibroblastic osteoscarcom) • Tumor grade, margin details, percent necrosis, vascular invasion

49. Peri-Operative Form (8.1 – 8.2) • To be completed prior to discharge • Collects details of hospital stay (i.e., catheter use, number of patients in room, dressing changes) • Record discharge details • Record wound vac details, if any

50. Follow-up Form (9.1 – 9.3) • Indicate Follow-Up Number • Ensure patients have pre-arranged appointments • Call “no shows” • Methods Centre will send lists of patients with upcoming follow-ups in bi-weekly QC reports