The Cardiovascular Inflammation Reduction Trial (CIRT) Investigator and Coordinator Teleconference March 6, 2014 Elaine Zaharris CIRT Project Manager Brendan M. Everett, MD, MPH CIRT Clinical Endpoints Committee Chairman Assistant Professor of Medicine, HMS Director, General Cardiology Inpatient Service, BWH

Agenda for Call Recruitment Overview – Elaine Zaharris Endpoint reporting and adjudication - Brendan M. Everett, MD Q and A

Recruitment Overview Sites Participants 474 interested 302 with IRB approval 270 ready to screen 190 with 1+ participants screened 114 with 1+ participants randomized Participants 1051 Screened 370 Randomized (as of February 28, 2014)

Agenda for Call Recruitment Overview – Elaine Zaharris Endpoint reporting and adjudication - Brendan M. Everett, MD Q and A

Variable Dose Methotrexate Simplified Flow Diagram – Five Phases to the Trial Cardiovascular Inflammation Reduction Trial (CIRT) 1 2 3 4 5 5 Week Open Label Run-In 4 Month 15mg MTX Versus Placebo 3 to 5 Years Variable Dose Methotrexate Versus Placebo Phase 3 Month Washout Phase V5 MI Stroke CV Death Other Endpoints M15 M20 M5-M10-M15-M20 MI/MVCAD T2DM or Metabolic Syndrome 5 10 15 P15 P20 P5-P10-P15-P20 Office Visits V1 V2 V3 V4 V5 V6 V7 V8 VN VF Safety Eval Banked Plasma Enrollment Pre-randomization Month 8 Month 24

Goals Describe and define the key clinical endpoints of the trial Describe the process for collecting clinical endpoints Describe what clinical documentation is required to adjudicate or confirm those events

Summary of Key CIRT Endpoints Adjudicated Endpoints MI Stroke Cardiovascular death Non-cardiovascular death Arterial revascularization Hospitalization for heart failure Unstable angina requiring unplanned revascularization Other Endpoints Atrial fibrillation Type 2 diabetes Aortic stenosis Peripheral artery disease DVT/PE Sleep Apnea Age-related macular degeneration Retinopathy/Nephropathy

Endpoint Reporting Be alert to endpoints that look like an AE on first blush Should that shortness of breath be reported as a PE? Or as CHF? Should that elective heart surgery be reported as revascularization? Be alert to endpoints that occur during an admission for an SAE Atrial Fib in the context of a pneumonia

Endpoint Reporting Be alert to endpoints that are easily missed Heart failure causing myocardial injury that should be adjudicated as a possible MI Elective coronary revascularization (outside of the context of an MI or an ACS) Episodes that may not have prompted hospitalization (e.g. atrial fibrillation)

Clinical Documentation The CEC may ask for more clinical information If they require more information to complete adjudication for the reported event If they suspect another type of event that might not have been reported Other reasons

Goals Describe and define the key clinical endpoints of the trial Describe the process for collecting clinical endpoints Describe what clinical documentation is required to adjudicate or confirm those events

How do I report an endpoint? Routine Follow-up Visit Complete Adverse Event/Endpoint Form Primary/Secondary/Tertiary Event Recorded Complete Endpoint eCRF Collect Clinical Documentation FAX or email to Data Coordinating Center

Routine follow-up

Adverse Event Form

Adverse Event Form (cont’d) Occurrence of a PRIMARY ENDPOINT leads to temporary discontinuation of study drug Occurrence of a SECONDARY ENDPOINT does NOT necessarily lead to discontinuation of study drug

Endpoint eCRF - MI

Clinical Documentation Checklist Myocardial Infarction Sent to BWH Unavailable Comment Admission history   Discharge summary Cardiac biomarker laboratory values and normal ranges ECG (baseline, pre-event) ECG (event) Imaging reports (echo/stress echo, radionuclide imaging, angiography, CT, MRI etc.) Procedure notes (PCI, CABG, other) Other Checklists for other clinical endpoints are included in the Manual of Operations

Case Example 1 Mr. S, a 65 yo man doing well at Visit 5 He is hospitalized for congestive heart failure He is diuresed with IV lasix, improves, and is discharged An AE/Endpoint form is completed reporting his Hospitalization for Heart Failure He resumes study drug after being discharged from the hospital, as directed by the algorithm

Case Example 1 Mr. S, a 65 yo man with heart failure The CEC reviews his record and agrees that his admission meets the study-specific definition for a HF admission However, they note a modest rise and fall of his troponin during his heart failure admission Here, they can do one of two things Notify you and request addition records Adjudicate a possible MI, if they believe they have adequate records Decide it’s not an MI and ignore the troponin

Case Example 2 Ms. T, a 70 yo woman who is admitted with unstable angina Her troponins are normal She is sent for catheterization An attempt is made to open a lesion in the distal RCA The attempt is abandoned after failure to deliver the balloon to the lesion

Case Example 2 Should you report this event? YES! How should it be reported? Hospitalization for unstable angina requiring unplanned revascularization What if the patient had a troponin T of 0.08 ng/mL after the procedure (URL < 0.01)? Should the study drug be temporarily discontinued?

Case Example 3 55 yo M with known MV prolapse and severe MR complains of progressive dyspnea He has no other symptoms or signs of heart failure A decision is made to move to MV repair The repair happens on an elective basis 4 weeks later

Case Example 3 How should this event be reported? As an SAE? As an endpoint? What if he had MV repair and single vessel CABG? Should his study drug be temporarily stopped?

Agenda for Call Recruitment Overview – Elaine Zaharris Endpoint reporting and adjudication Brendan M. Everett, MD Q and A