1. 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

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

3. 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)

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

5. 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

6. 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

7. 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

8. 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

9. 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)

10. 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

11. 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

12. 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 to Data
Coordinating Center

13. Routine follow-up

14. Adverse Event Form

15. 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

16. Endpoint eCRF - MI

17. 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

19. 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

20. 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

22. 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

23. 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?

24. 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

25. 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?

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