Case Report Form Start-up Meeting March 25, 2010 Kingston, ON

Formats Web-based Central Randomization System (CRS) Web-based Central Randomization System (CRS) (Includes screening, pre-randomization and randomization) (Includes screening, pre-randomization and randomization) Paper-Based Case Report Form Paper-Based Case Report Form (Includes baseline, daily data, antibiotics, microbiology, study intervention, mechanical ventilation, infection adjudication and outcomes) (Includes baseline, daily data, antibiotics, microbiology, study intervention, mechanical ventilation, infection adjudication and outcomes)

Central Randomization System Logs all screened patients Randomizes eligible, consented patients Pharmacy access to prepare study treatment

Central Randomization Process SCREEN NEW PATIENT Does NOT meet all Inclusion Criteria. Will NOT be saved on CRS Form 1 Inclusion Criteria Form 2 Exclusion Criteria Patient Eligible Form 3 Pre-Randomization Meets at least one exclusion criteria. Data entry complete. Consent NOT obtained. Enter reason why. Data entry complete. Form 4 Randomization

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CRF pg. 8-9 Pre-Randomization—Consent = Yes Pre-Randomization—Consent = No

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Paper-Based CRF Once the patient has been randomized, all subsequent data collected should be entered onto the paper-based CRF Once the patient has been randomized, all subsequent data collected should be entered onto the paper-based CRF Instructions Data Entry Page

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CRF pg To be collected within the first 24 hours of ICU admission

To be collected from Study Day 1 until ICU discharge, death or 28 days post randomization. Exception: Patient discharged to the ward < 14 days from randomization, continue until end of study day 14 CRF pg

CRF pg To be collected from Study Day 1 until ICU discharge, death or 28 days post randomization. Exception: Patient discharged to the ward < 14 days from randomization, continue until end of study day 14

To be collected from Study Day 1 until Day 14 (unless patient dies or is discharged from hospital. CRF pg

Protocol Violations Started open-label antifungal therapy Started open-label antifungal therapy Dosing error Dosing error Accidental unblinding Accidental unblinding Dose missed Dose missed Partial dose received Partial dose received Other, please specify Other, please specify

CRF pg To be collected from Study Day 1 until Day 14 (unless patient dies or is discharged from hospital. Should be reported to the Project Leader in “real time.”

CRF pg To be collected on Study Days 1, 3, 8 & 14.

CRF pg To be collected if: Initiated within 7 days of randomization Started in the ICU and continued in the ICU Started in ICU and continue past ICU discharge For patients receiving study treatment on the ward, collect until Study Day 17

CRF pg Do NOT record cultures that are NO GROWTH or CONTAMINANT Do NOT record SWABS To be collected if: Culture taken within 7 days of randomization Taken in the ICU For patients receiving study treatment on the ward, collect cultures taken until the end of Study Day 17

CRF pg If patient extubated < 48 hours, then mechanical ventilation is re-initiated, it is considered a continuation of previous ventilation.

CRF pg If patient discharged from ICU, then re-admitted within 48 hours, the re-admission is considered a continuation of the previous ICU stay.

Newly Acquired Hospital Infection Adjudication Site Investigator to make determination of a newly acquired infection based on antibiotic and microbiology data

Algorithm for Newly Acquired Infection Adjudication

If antibiotics started > 72 hr from randomization, 2 questions will be asked to help determine suspicion of hospital acquired infection

Suspicion of Hospital Acquired Infection 1. Is this antibiotic prescribed for prophylaxis? 2. Is this a substitute for an antibiotic previously ordered for an infection that occurred within 72 hrs of randomization? “NO” to both questions CLINICAL SUSPICION OF INFECTION Need Adjudication performed by Investigator or MD Delegate

If culture taken > 72 hr from randomization, 1 question will be asked to help determine suspicion of hospital acquired infection

Suspicion of Hospital Acquired Infection 1. Is this organism a manifestation of an infection that occurred within the first 72 hrs of randomization? “NO” to question CLINICAL SUSPICION OF INFECTION Need Adjudication performed by Investigator or MD Delegate

CRF pg Infection Adjudication Needs to be done for every suspicion that is triggered by an antibiotic or organism Categories of Infection & associated definitions found in Appendix 5

Is there an Infection? CRF pg. 34 This suspicion has already been adjudicated. 5 YES to Infection Refer to categories of infection for definitions of Definite, Probable & Possible 0 1 NO to Infection Indicate whether Probable or Possible NO

YES to Infection CRF Appendix 5

NO to Newly Acquired Infection

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