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

CERU Contacts SponsorDr. Daren Heyland Cell: Project Leader Janet Overvelde x6241 Data Manager Jennifer Korol x6051

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

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

Pre-Study Activities

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

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

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

CRS Access Log Implementation Manual pg. 10

Screening & Randomization

Inclusion Criteria Implementation Manual pg. 14

Entering screening data for a new patient:

Drop-down Check boxes

Exclusion Criteria Implementation Manual pg. 18

Eligibility Confirmation Should have documented confirmation from MD regarding patient eligibility Should have documented confirmation from MD regarding patient eligibility 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 at hrs. All questions & concerns addressed with SDM at this time. Copy of consent given to SDM. Date/time of entry: ____________ Signature of writer: ____________

Consent = NO Indicate the reason why consent was NOT obtained

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 Site Investigator or delegate i.e. sub investigator or research nurse Must be specified on the Delegation of Authority Log Must be specified on the Delegation of Authority Log Implementation Manual pg. 21

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

Explain the Study Procedures Explain VAP and treatment of identified bacterial organism as standard of care Explain VAP and treatment of identified bacterial organism as standard of care Presence of Candida “yeast” in the sputum, usually NOT treated 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. 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.

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

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

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

Consent Tools Consent template Consent template ICF Essential Elements Checklist ICF Essential Elements Checklist Sample Medical Chart entry Sample Medical Chart entry

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

Study Procedures Study Procedures Manual

MD Orders Implementation Manual pg. 26

Study Intervention Antifungal Therapy (anidulafungin and fluconazole) OR Placebo

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

Study Intervention: Placebo arm Normal saline OR D5W Normal saline OR D5W

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

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

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

Initiating Study Treatment 1. Following randomization, notify the Pharmacy 2. Pharmacist will determine treatment code by logging into CRS (UNBLINDED) 3. Pharmacy prepares study treatment 4. Administration of study treatment should start within 2 hours of randomization

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

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

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

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

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

Sample Types Vacutainer tubes will be provided to the sites Vacutainer tubes will be provided to the sites

Sampling Schedule

Lab Responsibilities Local LPS Stimulation LPS Stimulation Blood Processing Blood Processing Storing Frozen samples Storing Frozen samples Shipping samples to Central Lab in Ohio 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

Data Collection

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

Study Days Study days defined according to the ICU flow sheet: 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…

ICU flow sheet from Implementation Manual pg. 35

Source Documentation Required Documents Required Documents Patient Folders Patient Folders Worksheets & other data collection tools Worksheets & other data collection tools Health Canada requires study documentation be retained for 25 years

Study Tools Patients Folders Patients Folders Laminated reference cards Laminated reference cards Worksheets Worksheets

Patient ID List To be kept confidential To be kept confidential Enables identification of CANTREAT study patiaents at the site Enables identification of CANTREAT study patiaents at the site Required as per Health Canada and ICH GCP Required as per Health Canada and ICH GCP

Study Resources Project Leader Project Leader