1. PI and Coordinator Webinar
January 22, 2019

2. Newsletter
Latest newsletter sent out last week; please review for lots of important information
Enrolment updates
Recruitment tips
Science corner on timing of initiation of anticoagulation
AND MORE!

3. Enrollment In past 2 month: 487-> 610 patients consented
~40% eligible for randomization
122→ 149 randomized (25%)
24 eligible but not yet randomized

4. Top enrolling sites – by # randomized
Consented
United 10 29
OHSU 9
Iowa 23
Cincinnati 8 22
Penn 5 15
UF Shands 16
Univ. Illinois 4 7
MUSC 19
St. Mary's Grand Junction
Memorial Hermann 13

5. Top enrolling sites – by randomization rate
Randomized/Month
Consented/Month
United
1.13
3.28
OHSU
1.03
3.31
Iowa
0.92
2.35
Cincinnati
0.67
1.85
Emory
3.67
Barnes Jewish
0.63
Univ. Illinois
0.58
1.01
Penn
0.51
1.52
UF Shands
0.49
1.56
MUSC
0.48
2.28

6. Site startup In past 2 months: 103 → 114 sites released to enroll
52→ 59 sites with at least one randomization
89→ 97 sites with at least one consent

7. Coordinator and team heroes
The VA Ann Arbor team was the first site VA site to be released to enroll. James Burke, MD Karen Belanger, PSC Nick Buhay, SC
Kinga Aitken, the RCC Manager at the University of Utah and the Salt Lake City VA Coordinator, was a great resource and leader in navigating the VA system.
Real time nominations? (type in or pipe up!)
Kudos and thank you!

8. Central IRB Updates ARCADIA Continuing Review – Complete
Thanks to all for helping to get us through this process.
Be on the lookout for upcoming modifications:
Change in consent form to include apixaban reversal agent (andexanet alfa)
Other minor changes
Protocol modification

9. DSMB Update DSMB Meeting 12/7/19 No significant concerns
Proceed as planned
Recommendations
Enhance accrual
Consider modification of consent in light of ESUS trial results
Procedural recommendations for SAE reporting
Follow up in 6 months

10. Enrollment suspended at 2 sites
The ARCADIA team and/or the CIRB has the authority to suspend enrollment at a site if there are concerns.
Recently we have identified a couple of issues where we felt enrollment should be held temporarily.
The errors that were identified involved the informed consent process and study medication dispensing.

11. Informed Consent Process
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.

13. Screen failure logs
Establish a plan to be notified about ALL patients who present to the ED, Neurology inpatient service, Neurology outpatient clinics, or any associated rehabilitation facilities.
Include patients who are transferred from an outside facility with suspected stroke.
Include patients seen in outpatient facilities for second opinions, or who do not come through the ED.
Screen all stroke patients to identify those that are ESUS (Embolic stroke of undetermined source).
Screen failure logs should include ONLY patients that have ESUS

15. “Failure to enroll” warning notices
Some sites are beginning to see warning notices ( s)
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!

16. Re-training
If your site has not consented any subjects in previous 3 months you will receive an 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 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.

17. 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.

18. 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.

19. Open mike… Who is having challenges? Tell us what/how/where/why
High enrolling sites may have suggestions…

20. Echo issues Echocardiograms in ARCADIA serve 2 purposes:
Determine whether patient meets ESUS criteria and thus can be consented for screening (use TTE or TEE; whatever local protocol is for establishing ESUS)
Determine the left atrial size for purposes of determining presence/absence of atrial cardiopathy (i.e., eligibility for randomization): requires TTE ONLY
Note that patient can still become eligible based on the EKG or NT-proBNP criteria if no TTE done
ONLY TTEs should be sent to the echo core
These should be sent in batches, with one patient per DVD

21. Echo issues
Reach out to your echo lab to ensure the images are saved in DICOM format and that they are editable.
Studies should be obtained in DICOM format and downloaded to DVD as such; a DICOM directory should be generated in the process
Remove any protection that makes studies not editable before downloading them to the DVD
If studies are originally in DICOM format, they should be exported as such, even if de-identification is lost in the process
Only one study should be downloaded to each DVD

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

23. ← LA Diameter ← Height ← Weight ← LA Diameter Index calculated for you
Range expected 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

24. Emergency unblinding
Unblinding can occur if a participant has an emergency clinical need to know if they are taking apixaban vs. aspirin. These clinical emergencies include:
• An acute ischemic stroke qualifying for use of tPA
• A significant bleeding event, such as a major hemorrhage
• The need for emergency surgery for any reason
BUT REMEMBER THAT unblinding may not be necessary IF KNOWING STUDY DRUG STATUS WILL NOT CHANGE MANAGEMENT (i.e., if all of the following conditions are met):
• The subject or surrogate can confirm that no study drug has been taken for the past 48 hours;
• The subject’s renal function is normal (GFR ≥60); and
• The subject’s INR and PTT values are normal.

25. Emergency unblinding
For any emergency request for unblinding, the site investigator OR emergency care provider should:
Call the ARCADIA hotline
Patients will be given a wallet card with the hotline number on it
Discuss case with ARCADIA PI on call, who will evaluate the clinical scenario promptly, including review of conditions whereby unblinding may not be necessary
If the PI on call agrees with the need for unblinding, the ARCADIA hotline PI will
• Take down Subject ID, Kit ID or bottle ID (s) AND callback number for local PI/emergency care provider
• call the WebDCU™ Emergency Randomization Hot Line at
• confirm the need for unblinding with NDMC staff, and reason for unblinding
• provide the call back number for the NDMC to reach the site investigator or emergency care provider directly
The NDMC will then
• unblind the participant’s treatment assignment in WebDCU™
• call the site investigator or emergency care provider
• provide the randomized treatment assignment information

26. Emergency unblinding Wallet cards Be sure to give these to patients
ARCADIA
ALERT CARD
Subject Name: __________________________________________
Subject ID#: ____________________________________________
I am participating in the ARCADIA Trial, a randomized, blinded clinical research study for stroke prevention.
I am taking either apixaban (Eliquis) or aspirin
If I require medical attention at any time, please call the Emergency Contact, Primary Physician, and/or ARCADIA Trial Contact numbers listed on the reverse side of this card.
ARCADIA TRIAL ALERT CARD
For an emergency that requires knowing whether I am taking apixaban (Eliquis) or aspirin for this study, please call the 24-hour ARCADIA TRIAL HOTLINE at
For all other emergencies:
Local ARCADIA Team:_____________________________________
Name Emergency 24 hr #
Primary Physician:_______________________________________
Wallet cards
Be sure to give these to patients
Check to be sure that patients have these at f/u visits
Reversal agents will not be provided by the study.
The site study team will also need to fill out the appropriate CRF within 72 hours.
The ARCADIA hotline PI will remain blinded via the above procedures.
Subjects who are unblinded will not be resumed on study drug but will continue to be followed and analyzed per the intent-to-treat principle.

27. Hotline 24-hour telephone hotline
Please use it for any urgent questions
Eligibility, randomization, unblinding, etc
( AR-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 with non-urgent questions

28. Recruitment challenges and FAQs

29. Recruitment challenge #1
62 year old man presented with three days of progressive left leg weakness followed by left arm weakness. He took ibuprofen, thinking it might help. He fell twice, prompting ED visit.
He had a history of hypertension and hyperglycemia, but had not been taking any medications.
Upon arrival to ED, stroke code called. He was alert with out aphasia. Exam notable for mild left inattention, left facial paresis, left arm drift with impaired finger tap, left leg mild weakness. There was visual and tactile extinction to double simultaneous stimulation. NIHSS 6.

30. Recruitment challenge #1
? lacune
Head CT done in ED

31. Recruitment challenge #1

32. Recruitment challenge #1

33. Recruitment challenge #1
From ARCADIA I/E criteria, definition of ESUS:
Stroke that is not lacunar. Lacunar is defined as a subcortical (this includes pons and midbrain) infarct in the distribution of the small, penetrating cerebral arteries whose largest dimension is ≤1.5 cm on CT, ≤2.0 cm on MRI diffusion images, or ≤1.5 cm on MRI T2-weighted images.

34. Recruitment challenge #2
52yo man who presented with left hemiparesis.
He was in his usual state of health and awoke with left arm heaviness and had difficulty lifting objects. He also noted that he had "less bounce" in left leg when walking but was able to walk. He thought symptoms were muscular and deferred presentation. He came in after symptoms did not resolve. He also noted that he had been bumping into things with his left side since symptom onset but denied vision changes.
PMH of HTN, hyperlipidemia, and prior stroke (left internal capsule, 2013, treated with tPA, no residual symptoms).
He had run out of his BP medications one week prior and had stopped his diuretic one month prior.
In ED, BP recorded as 203/159, given 10 IV labetalol, repeat SBP 175.
Neurological exam notable for mild left hemiparesis. NIHSS 3.

35. Recruitment challenge #2
?Eligible

36. Recruitment challenge #2
From ARCADIA I/E criteria, definition of ESUS:
Stroke that is not lacunar. Lacunar is defined as a subcortical (this includes pons and midbrain) infarct in the distribution of the small, penetrating cerebral arteries whose largest dimension is ≤1.5 cm on CT, ≤2.0 cm on MRI diffusion images, or ≤1.5 cm on MRI T2-weighted images.

37. Recruitment challenge #2
By superimposing a digital conventional angiogram to a brain computed tomographic angiogram from the same patient one can observe the brain territories supplied by penetrating arteries (blue arrows), cortical arteries (red arrows) and medullary arteries (yellow arrows). An embolus reaching the convexity surface of the brain may cause a small subcortical infarct in the territory of the medullary arteries (B) or distal superficial arteries supplying the cortical surface (C).

38. What is ESUS?
If you have questions about complicated patients, or are unsure of the diagnosis of ESUS in any particular patient, please feel free to get in touch with Irene, the PIs, or us at

39. FAQs
Clarifying inclusion criteria regarding extra/intracranial atherosclerosis. 
Question: If the patient has > 50% stenosis of the artery supplying the area of ischemia, they are excluded.  So then patients with complete occlusions would be excluded, correct?  And if the person had an occlusion, and received thrombectomy, would they still be excluded?
Response: It is correct that if they have > 50% stenosis of the artery supplying the ischemia they would be excluded. That includes a total atherosclerotic occlusion.
The PI will need to distinguish between a complete occlusion due to intrinsic atherosclerotic disease vs occlusion due to an embolism from a distant source, like the heart.
If after thrombectomy, there is no longer an occlusion, that would imply an embolism that has been extracted, rather than underlying atherosclerosis as the cause.
However, if they had a thrombectomy and this reduced the stenosis to < 50% they could be considered for enrollment.

40. FAQs
Question: We are screening a potential ARCADIA patient who has a small stroke on head CT. The PI estimated the infarct to be just at 1.5 cm. We want to confirm that this stroke qualifies based on size before proceeding with any other screening procedures.  
Response:
The size criteria only apply if it’s a subcortical, deep infarct.
If it’s a superficial, cortical infarct, there is no size issue.
If this is a deep, subcortical infarct, then it may or may not be eligible based on size.
Remember that there are other reasons why it could qualify:
multiple simultaneous small deep infarcts
lateral medullary infarcts
cerebellar infarcts

41. FAQs
Question: We have a possible candidate for ARCADIA. Per the echo, patient has mild mitral valve stenosis.  Our doctors think the stroke is cryptogenic and not cardioembolic.  The patient is currently wearing a 30 day Holter. 
It looks like in the protocol that having mitral stenosis (under the explanation of “no major risk cardioembolic source of embolism”) would exclude them. Is this correct?   
The patient also has moderate to severe mitral regurgitation.  It doesn’t look like that is an exclusion, but want to double check.
Response: Mitral stenosis is considered an exclusion criterion. We plan to change the protocol to allow mild MS. Stay tuned!

42. FAQs
Site Question: We have a patient who was admitted at an outside hospital for stroke on 9/8. The patient was seen at our neuro clinic on 11/12. His MRI on 11/12 showed a new cortical stroke. What would be day of onset for randomization ? Would you use the day the stroke for identified in the office (11/12) or something else?
Response: If it was an incidental finding, without a new clinical diagnosis of stroke, then would stick with the prior stroke date (9/8) as the incident date. If there really was a new stroke on the 11/12 visit, then that would be the start (i.e., stroke) date. The patient would have a history of stroke 2 months prior.
Site: Patient did not have any new stroke symptoms corresponding to his new stroke on the recent MRI Brain.
Response: What was type of the initial 9/8 stroke?
Site: The symptomatic stroke was lacunar.
Response: Not eligible.

43. FAQs
Others? (type in or pipe up…)

44. Thank you so much for your efforts to make ARCADIA a success!!
Next steps
Actively screen
Bring back randomization-eligible patients
Send us feedback—we will make changes as needed to make this trial successful!
Thank you so much for your efforts to
make ARCADIA a success!!

45. Feel free to reach out! 24-hour telephone hotline
Please use it for any urgent questions
Eligibility, randomization, unblinding, etc
( AR-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 with non-urgent questions