PI and Coordinator Webinar November 27, 2018

Site startup In past month: 100 → 103 sites released to enroll 45 → 52 sites with at least one randomization 79 → 89 sites with at least one consent

ARCADIA Continuing Review - Update 113 sites CIRB approved for ARCADIA All 113 have submitted at least some documents for the CR Of the 113, 102 (90%) are ready with all information submitted Emails and/or phone calls have been sent to sites with missing information New goal is all ready by 11/28/2018.

ARCADIA Continuing Review - Update If you are unable to obtain a new signed StrokeNet COI from any of your team members listed on the DOA by 11/28- Please edit your DOA and remove these people. After the continuing review, you can add these team members back on your DOA once they have signed the COI. They will not be able to participate in any study activities during that period of time when they are not listed on your DOA.

Enrollment In past month: 404 -> 487 patients consented ~40% eligible for randomization 107 → 122 randomized Today 51 eligible but not yet randomized

Top Sites - Overall

Top Sites - Rand/m

Enrollment ideas Local colleague referrals Given the 4m window, regional referrals to sites possible Give talks at key regional hospitals? Slides available… Early/in hospital identification Reminder of modification that visits do not need to all be in person MOP modifications 14.1 FOLLOW-UP VISIT 1 (DAY 30): This visit can be done via telephone or other HIPAA- compliant telehealth technology 14.2+ FOLLOW-UP VISIT 2+ - This visit should be done in person but can be done via telephone or other HIPAA-compliant telehealth technology if: An in-person visit cannot be arranged after repeated efforts, and Study drug can be shipped directly to the patient by your site, following your local institutional policies and pharmacy board laws.

Enrollment ideas Adding additional sites: StrokeNet, non-StrokeNet, possibly Canadian If you have sites that are interested in participating, let us know and have them complete a site selection survey. If you have clinics or rehab facilities near you where you could possibly screen subjects for ARCADIA, let us know and we can work with you on what you would need to do to add them.

“Failure to enroll” warning notices Some sites are beginning to see warning notices (emails) The original Clinical Trial Agreement specifies that sites can be put on probation for: Failure to randomize a patient for three months Failure to complete required documents/approvals/processes Continued failure to enroll means: Retraining requirement (certifying that you watch the start-up slides again) Calls with PIs Eventually, possible termination of participation We are focused initially on sites that have not CONSENTED any patients (rather than randomized) We want all sites to succeed!

Re-training If your site has not consented any subjects in previous 3 months you will receive an email notification that retraining will be required if you do not consent any subject within the next 6 weeks. The retraining will consist of the Site PI reviewing the Investigator slides on the campus training website https://webdcu.musc.edu/campus/ and reviewing the trial details with his/her team. The Site PI will be required to sign a re-training attestation form also located on the campus training website and uploading this to WebDCU. The ARCADIA team may also request a phone call with the site to discuss screening and recruitment strategies.

DONE LOCALLY DONE LOCALLY

ECHO Measure LA Diameter vs. LA Diameter Index Complicated…. DO NOT CALCULATE!!!!

← LA Diameter ← Height ← Weight ← LA Diameter Index calculated for you Range expected 2 - 7 cm If outside range, please double √ If you are unsure how to find this measurement or have any questions, please do not hesitate to reach out. ← LA Diameter ← Height ← Weight ← LA Diameter Index calculated for you

ECHO report sample…

Informed consent monthly highlight Each webinar we have been highlighting issues that we have identified with informed consent documents. The informed consent process is more than just a signature on a form, it is the process of information exchange and measuring a subject’s understanding. The consent document should be the basis for this exchange, which makes it imperative that the document is signed and dated accurately.

Informed Consent (cont) Consent should be obtained by someone delegated this responsibility on your DOA The subject or LAR should sign and date the consent on the appropriate line. If the subject or LAR makes a mistake have them cross it out and initial the change. The investigator/coordinator obtaining consent should sign and date the consent immediately after the subject or LAR signs.

Example of a informed consent checklist created by one of our RCCs This document is saved in WebDCU™ in the ARCADIA toolbox

ARCADIA Study Drug Assignment Remember the study kits shipped to your site are not patient specific. Follow-Up visit procedure to obtain a new kit assignment Complete Form 512 Study Drug kit assignment Enter weight and creatinine -if done Complete Form 513 Study Drug Kit Dispensing Complete Form 514 Study Drug Usage and Adherence

Corrective Action/Preventative Action Plan If you identify an issue or concern at your site, please notify us. You may be asked to create a CAPA plan. We will work with sites and their RCCs on an appropriate plan. A CAPA plan is not meant to be punitive. The ultimate goal is to protect the safety of the subjects and the integrity of the trial.

Study Drug Related CRFs Ideally it is best not to randomize a subject until they are discharged from rehab and able to take study drug If you find out after randomization that the subject is at a facility that will not allow them to take study drug, do not assign study drug For Q01 ‘Subject requires a Drug Kit’ on F512, mark ‘No’ and explain why in the general comments. If subject is later discharged from rehab, study drug can be assigned and dispensed at that time. General comments can be edited to explain why drug is being assigned/dispensed at the later date (after the initial study visit date). Similarly, if study drug was assigned, but subject withdraws consent before drug can be given to subject For Q06 ‘Drug kit dispensed’ on F513, mark ‘No’ and explain in the general comments.

AE CRF Change Verbatim AE Name Select Appropriate corresponding MedDRA Term

Coordinator heroes Kudos and thank you! Kinga Aitken for expediting shipping of ECHOs to the ECHO Core for QA purposes Real time nominations? (type in or pipe up!) Kudos and thank you!

FAQs Intracranial stenosis, but multifocal infarcts Atrial flutter Others? (type in or pipe up…)

Please complete CCS form for recurrent stroke Only for cases of recurrent ischemic stroke after randomization—not needed for baseline (index) stroke! Website for CCS - https://ccs.mgh.harvard.edu/ccs_title.php Please cut and paste text from CCS website to WebDCU Having data on recurrent stroke subtype will help us tremendously! New set of slides outlining process to be placed in WebDCU

What do recent ESUS trials mean for ARCADIA? NAVIGATE ESUS announced last October, published in May RE-SPECT ESUS announced October 2018 at WSC Both trials found no benefit of anticoagulation in unselected ESUS Reinforces importance of ARCADIA and search for tailored treatment strategies

Prior evidence for Rx heterogeneity

New evidence for Rx heterogeneity

Our interpretation of ESUS trials No current indication for anticoagulation in ESUS Compelling evidence for subsets that will respond to anticoagulants We should not be nihilistic about finding better, more tailored preventive treatments It is now even more important than ever to complete ARCADIA!

Feel free to reach out! 24-hour telephone hotline Please use it for any urgent questions Eligibility, randomization, unblinding, etc 1-877-427-2234 (1-877-4AR-CADI): useful to save in your cell phone The hotline automatically calls the four PIs in succession Please let it ring And call back if no luck—one of us will pick up! Please email arcadia@ucmail.uc.edu with non-urgent questions