Study Procedures & Operational Issues

1. Study Procedures & Operational Issues Start-up Meeting March 25, 2010 Kingston, ON

2. CERU Contacts

3. Role of Study Coordinator Regulatory Screening & Randomization Pharmacy Communication Blood Sample Draws Data Collection Monitoring Study Intervention Administration Monitoring & Identifying SAEs Protocol Violation Reporting

4. Core Lab • LPS Stimulation • Blood Processing • Shipping to central lab in Ohio, USA Site Investigator • Confirm patient eligibility • Infection adjudication • SAE Reporting Research Coordinator Pharmacy • Checking treatment allocation • IP preparation & dispensing • Dose adjustments for renal disease • IP Accountability CANTREAT Teamwork Micro Lab • Identify yeast • Confirm presence of Candida in qualifying respiratory samples • Sending respiratory samples to OPHL

5. Pre-Study Activities

6. Required Documentation • REB Approval • REB Approved Consent • Fully-Executed Site Agreement • Team Qualifications • CVs & Licenses • Delegation of Authority • Overall • Pharmacy • Local Laboratory • Laboratory Accreditation & Reference Ranges • CRS Access Logs • Study Coordinators • Pharmacy Implementation Manual pg. 9

7. Delegation of Authority Must be kept up to date throughout the duration of the study. Implementation Manual pg. 9

9. Training • All study related training should be documented. • Any study related training initiated at the site should be documented and a copy sent to CERU PL

10. CRS Access Log Implementation Manual pg. 10

11. Screening & Randomization

12. Inclusion Criteria Implementation Manual pg. 14

13. Entering screening data for a new patient: Only enter patients who meet Inclusion Criteria

14. Drop-down Drop-down Check boxes

15. Exclusion Criteria Implementation Manual pg. 18

17. Document in Medical Chart Patient enrolled in CANTREAT study. Patient randomized to the study at hrs. Patient met all the inclusion criteria and none of the exclusion criteria. Eligibility confirmed with Dr. ______________. Consent obtained from _____________ (relationship to pt) on dd/mmm/yyyy athrs. All questions & concerns addressed with SDM at this time. Copy of consent given to SDM. Date/time of entry: ____________ Signature of writer: ____________ Sign Incl/Excl Worksheet Eligibility Confirmation • Should have documented confirmation from MD regarding patient eligibility OR

18. Consent = NO Indicate the reason why consent was NOT obtained

19. Obtaining Informed Consent Timing: When? Consent must be obtained within 96 hrs of the Candida +ve respiratory specimen sample time Who obtains consent? • Site Investigator or delegate i.e. sub investigator or research nurse • Must be specified on the Delegation of Authority Log Implementation Manual pg. 21

20. Whom to Get Consent from? • Patients are often incapable given acuity of illness • Substitute decision maker (SDM) or patient’s legally acceptable representative

21. Explain the Study Procedures • Explain VAP and treatment of identified bacterial organism as standard of care • Presence of Candida “yeast” in the sputum, usually NOT treated • Purpose of the study is to determine if treating Candida, with antibiotics effective against Candida, in addition to the usual antibiotics administered for lung infections will improve the outcome of these infections.

22. Explain Study Procedures • Study Treatment: • GROUP 1: Standard ICU Care + antibiotic for Candida • GROUP 2: Standard ICU Care + Placebo (placebo oral solution or a bag of salt water intravenously) • Risks & benefits • Blood will be taken on days 1, 3, 8 & 14 to help us understand how • Follow up at 90 days to check on patients status

23. If Consent Obtained, Remember to: • Ensure SDM has signed and dated the ICF • Place original in study files, copy to medical chart & copy to SDM • Write a note in the medical chart stating: • Name of SDM who provided consent, relation to patient • Date and time that consent was received • Time that patient was randomized

24. Telephone Consent • Document in the medical chart that consent was obtained via telephone before the patient was randomized • Follow up with the SDM to see that the ICF is signed as soon as possible.

25. Consent Tools • Consent template • ICF Essential Elements Checklist • Sample Medical Chart entry

26. Consent = YES We are interested in knowing any academic studies the patient is co-enrolled in.

27. Study Procedures Study Procedures Manual

28. MD Orders Implementation Manual pg. 26

29. Study Intervention Antifungal Therapy (anidulafungin and fluconazole) OR Placebo

30. Study Intervention: Active Treatment Arm Products provided by Pfizer Generic name: anidulafungin Trade name: Eraxis™ Generic name: fluconazole Trade name: Diflucan Oral administration IV administration

31. Study Intervention: Placebo arm Normal saline OR D5W

32. IV Administration • Infusion solution must be administered within 24 hours • Should be stored at room temperature • To be infused over 2-4 hours, as per pharmacy instructions

33. Oral Administration • Via NG tube or orally • Administer 40mL OD • Should be stored at room temperature

34. Duration of Study Treatment • Administered once daily • Routes of administration: IV or PO • Total of 14 days • Continue if discharged to the ward Exception: patients discharged from hospital before 14 days of study treatment completed, discharge day = last day of study treatment Implementation Manual pg. 27-29

35. Initiating Study Treatment • Following randomization, notify the Pharmacy • Pharmacist will determine treatment code by logging into CRS (UNBLINDED) • Pharmacy prepares study treatment • Administration of study treatment should start within 2 hours of randomization

36. Things to consider once patient starts to receive IP: • Study Treatment Compliance • Presence of renal disease or changes in renal function during the treatment period • Open-label antifungal use

37. Patient Randomized IP initiated within 2 hours IP administration initiated: Anidulafungin (Eraxis) OR Placebo IP administered via IV route minimum of 72 hrs Compatible with normal saline and DW5 Speciation and susceptibility results from OPHL, sent to Pharmacy to adjust IP per protocol “Active” treatment arm will be switched to fluconazole if organism is susceptible

38. Dose adjustments for renal disease. SC reports any changes is renal function to Pharmacy Anidulafungin = NO changes required Fluconazole = changes required If patient switched to fluconazole following switch to oral form, fluconazole loading dose should be IV route, then can proceed with oral If gastro-intestinal tract functional, can switch IP to oral route Open-label antifungals clinically indicated, STOP IP & report Protocol Violation Last day of IP administration is Study Day 14 (including patients discharged to the ward

39. Protocol Violations • Used to report deviations in compliance with IP • Should be reported to CERU in “real time”

42. Blood Draws • Type of samples • Sampling schedule • Local Lab Procedures • Central Lab Implementation Manual pg. 30

43. Sample Types • Vacutainer tubes will be provided to the sites

44. Sampling Schedule

45. Local LPS Stimulation Blood Processing Storing Frozen samples Shipping samples to Central Lab in Ohio Central Provide sites with LPS stimulation media Provide sites with supplies Provide sites with shipping containers Analyze samples received from sites Lab Responsibilities

46. Data Collection

47. More on Paper CRFs • 2-part NCR paper • Top copies of CRFs will be sent to CERU • Bottom copies to remain at the site

48. Study Days • Study days defined according to the ICU flow sheet: Study Day 1 = Randomization Day Study Day 2 = Next ICU flow sheet Study Day 3 = Next ICU flow sheet Study Day 4 = etc…

49. ICU flow sheet from 0700-0659 Implementation Manual pg. 35