ENGAGE AF – TIMI 48 Event Reporting Refresher Training

1. ENGAGE AF – TIMI 48 Event Reporting Refresher Training March 2012 Updates

2. SAE/Endpoint Reporting Since the original training in April 2010, there has been an additional eCRF added to the InForm database: the VKA dosing error CRF Please use this form to report any VKA overdose or dosing error events. Suspected edoxaban/placebo overdose events should be reported on the SAE CRF. Please refer to the Safety Reporting Site Reference Guideor contact the SAE hotline if you have any additional questions 2

3. Event Reporting Decision Tree Event 1- Cerebrovascular Event 2- Systemic Embolic Events 3- Cardiac Ischemic Event 4- Bleeding (non-intracranial) Appropriate Endpoint page Yes Is it an endpoint? No Event of Special Interest page 5- Hepatic Events & Liver Enzyme 6- Bone Fracture 7- Malignancy 8-VKA Dosing Error Is it Event of Special Interest? Yes No SAE page Does it meet serious criteria? Any event which does not meet criteria of potential endpoint or event of special interest Yes No Endpoints, Events of Special Interest and SAEs must be reported in the EDC within 24 hours Non-serious AE page 3

4. Reporting of Overdose/Dosing Error Events Reporting Dosing Error Events: • Report suspected incorrect dosing of warfarin/placebo and/or open‐label vitamin K antagonist on VKA dosing error CRF. • If the dosing error is associated with bleeding, report the dosing error on the VKA dosing error CRF and the bleed on the BLEED CRF. • If the dosing error is associated with an elevated INR, describe the INR event in the VKA dosing error narrative; do NOT report the elevated INR as a separate event. • Blinded edoxaban/placebo overdose events should be reported on SAE CRF. IMPORTANT REMINDER: • An overdose event should NOT be reported if there is no evidence of an overdose or incorrect dosing, and only a bleed or an elevated INR was observed. • Elevated INR should only be reported as a separate event when there is not a confirmed dosing error or bleed event reported 4

5. SAE/Endpoint Reporting Do not report outcome or treatment as the event. • Hospitalization or death is NOT an appropriate SAE term • Report the reason for hospitalization or cause of death on the appropriate event CRF • ER visits and hospitalization of less than 24 hours should be reported on the HOSP CRF and not necessarily as SAEs or events of special interest • Report “hospitalization for unknown reasons” while following up with the patient on the HOSP CRF • EXAMPLE: “bleeding requiring hospitalization and transfusion” • Report “bleeding” on BLEED page • Include the additional details in the narrative; complete the supplemental eCRF pages for hospitalization and transfusion. • EXAMPLE: “percutaneous coronary angioplasty and stenting to the LAD 70% stenosis” • Report the diagnosis, “coronary artery stenosis”, not the procedure. 5

6. SAE/Endpoint Reporting Do not report outcome as the event. Fatal events should be reported on the DEATH CRF AND a corresponding SAE or event of special interest CRF • Report “death cause unknown” while obtaining more information. Once more information is available, update the event term accordingly. 6