1. PI and Coordinator Webinar
September 25, 2018

2. Enrollment In past month: 264 → 336 patients consented
42% eligible for randomization
73 → 92 randomized

3. Top enrolling sites Randomized Consented Iowa 9 18 United 8 23 OHSU 620
Cincinnati 15
Penn 4 10
Intercoastal 3 12
OSU
UF Shands
Memorial Hermann
University of Illinois

4. Site startup In past month: 108 → 113 CIRB submissions
101 → 114 CIRB approvals
89 → 97 readiness calls
87 → 95 sites released to enroll
33 → 39 sites with at least one randomization

6. Coordinator heroes Road Warrior:
A study subject was unwilling to come back in for a follow-up visit since he was depressed about a breakup with his girlfriend.
He was going to run out of study medication, so the coordinator drove 3 hours to Wyoming to do the study visit at the subject’s home.
Hero: Michael Dela Cruz at the University of Utah.
Kudos and thank you!

7. Presenting the study to potential patients
Experience at the University of Utah

8. Presenting the study to potential patients
Experience at the University of Iowa

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

10. Newsletter
Latest newsletter sent out last week; please review for lots of important information
Enrolment updates
What is ESUS?
How to handle anticoagulation for procedures
AND MORE!

11. “Failure to enroll” warning notices
Some sites may begin 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 can lead to:
Retraining requirement
Termination of participation
We will focus initially on sites that have not CONSENTED any patients (rather than randomized)
We want all sites to succeed!

12. Further Recruitment Efforts
Recruitment Innovation Center (NIH Center, part of National Center for Advancing Translational Science [NCATS])
Will be calling top and bottom performing sites to get more information about successful and unsuccessful strategies
Consider surveying patients who consent but then decide not to be randomized after eligible (this should not happen!)
May also consider surveying those who elect not to enroll at all
Site PIs educate local/referring physicians/hospitals
Grand Rounds, Lunch and Learn, etc.
Slides available
Patient-facing
Patient brochure
Video: will appear on-line for patients who may search after a stroke for information
Website
Other ideas?

13. Recruitment Focus: What is ESUS?
Some investigators have asked that we clarify what is meant by ESUS (Embolic stroke of undetermined source).
Diagnostic criteria initially published in landmark paper: Hart RG et al. Lancet Neurol 2014; 13: 429–38).
The diagnosis of ESUS requires evaluation to establish:
(1) Non-lacunar stroke detected by CT or MRI;
(2) Absence of extracranial or intracranial atherosclerosis causing >50% luminal stenosis in arteries supplying territory of infarction;
(3) No major-risk cardioembolic source of embolism based on TTE and >24 hour monitoring (i.e., AF/flutter, prosthetic valve, LVEF<30%, etc.); and
(4) No other specific cause identified (dissection, vasculitis, spasm, etc.).

14. What is ESUS? What tests are required to make a diagnosis of ESUS?
Making a diagnosis of ESUS requires a standard set of diagnostic tests.
It does not require exhaustive testing.
The tests required to make a diagnosis of ESUS are:
Brain CT or MRI: to exclude lacunar stroke
Imaging of both intracranial and extracranial arteries (via CTA, MRA, Doppler or invasive angiography): to exclude stenosis, dissection, vasospasm, etc.
12-lead EKG: to exclude AF/atrial flutter
Transthoracic echocardiography: to exclude major-risk source of cardiac embolism, such as AF/flutter, prosthetic valve, LVEF<30%, valve vegetation, etc.
Cardiac monitoring for >24 hours: to exclude AF/flutter (for purposes of ARCADIA, we allow cardiac telemetry

15. What is ESUS?
The following tests are NOT required, but may be done in individual cases at clinical team’s discretion, as appropriate, based on history/exam:
TEE
Monitored outpatient cardiac telemetry (MCOT) or implanted cardiac monitor
Blood or CSF tests for things like syphilis, lupus, endocarditis…
Fat saturated MRIs to exclude dissections or other unusual vasculopathies

16. What is ESUS?
How soon can a diagnosis of ESUS be made after presentation?
A diagnosis of ESUS cannot be made before 24 hours after admission, since the patient will need to have at least 24 hours of monitoring (or telemetry) without AF.
Unlikely that ESUS can be diagnosed definitively in the ED.
The diagnosis can be made on the second hospital day, however.
This would be an ideal time to consent the patient if no specific cause has been found. In some cases, but only when the history suggests an unusual diagnosis (e.g., dissection, vasculitis, lupus, syphilis, endocarditis, etc.) the clinical team may wish to wait until further testing can be completed.
This should be the exception, however.

17. What is ESUS? ESUS until proven otherwise!
One simpler way to think about the diagnosis is that ALL ischemic strokes can be considered ESUS until one of the specific other stroke causes is found.
ESUS is not a rare diagnosis: About 1/3 of strokes should be ESUS.
Thus, consider each patient a potential candidate for ARCADIA unless and until one of the following diagnoses is made:
Lacune
Vascular stenosis in territory of stroke vessel
Cardiac embolic source
Other definite specific cause.

18. What is ESUS? Cardiac telemetry
The original ESUS paper specified that cardiac monitoring had to include automated rhythm detection and that telemetry was not sufficient.
For the purposes of ARCADIA, however, telemetry is acceptable, if that is standard at your institution.
The PI simply needs to confirm that AF was not detected.
Additional monitoring can be done at discretion of clinical team, but you do not need to wait for results to approach patient.
If patient develops AF before randomization then they are no longer eligible to be randomized.
If they develop AF on monitoring after randomization then they should exit study treatment but continue follow-up (see MOP for details).

19. What is ESUS?
Lacunes
For the purposes of ARCADIA (see I/E criteria), “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. The following are not considered lacunes:
multiple simultaneous small deep infarcts
lateral medullary infarcts
cerebellar infarcts
All potentially eligible

20. What is ESUS?
Patients with ESUS can still have risk factors for stroke
It is important to distinguish between:
risk factors
and
causes
Patients with ESUS may still have risk factors, including hypertension, diabetes, smoking, hyperlipidemia, and family history.
These may be distinguished from proximate causes of stroke, such as carotid stenosis, atrial fibrillation, valvular vegetations, etc.
If there is no specific cause identified, then the patient is eligible, even if they have risk factors.

21. Related FAQ
Question: Is a patient eligible if they had a stroke while on hormone replacement therapy?
Answer:
Yes, HRT may be considered a risk factor for stroke. The risk of stroke is slightly increased in women who take HRT, but it is not considered a proximate cause of their stroke.
Some might consider HRT a risk factor for hypercoagulability, or suggest that the mechanism by which HRT causes stroke is through hypercoagulability.
However, one way to think of how to handle HRT or similar risk factors is whether it would lead you to prescribe anticoagulation for such a patient. If you would prescribe anticoagulation, then the patient should not be in ARCADIA. If not, then the patient is eligible.

22. What is ESUS?
Cancer
Some cancers are associated with a hypercoagulable state and increase stroke risk, but cancer is not generally considered a proximate cause of stroke.
Patients with cancer can be considered eligible.
Other issues may need to be taken into account in such patients:
are they able to participate in a stroke trial, or will they be receiving aggressive or experimental chemotherapy that may complicate the use of study medications?
What is their cancer-related prognosis and will they be able to follow up?
In some patients (e.g., adenocarcinoma or those at risk of DVT, an oncologist may want to prescribe anticoagulation, making them ineligible for ARCADIA.

23. Related FAQ
Q: I have a patient who had a colon resection for cancer in April of this year. Since he is called cryptogenic, it seems our doctor doesn’t see any concern for hypercoagulability due to the ca. Surprisingly to me, there isn’t any exclusion for ca in the protocol regardless of date. A1: There’s no doubt that cancer-related hypercoagulability contributes to stroke risk but these strokes still often meet criteria for cryptogenic or ESUS, so active cancer isn’t on its own an exclusion. A2: The other crucial factor is whether the treating primary MDs and oncologists are willing to have the patient randomized to apixaban vs aspirin. We don’t want the patient to be randomized only to have the oncologist insist on anticoagulation.

24. What is ESUS? Retinal emboli
Retinal emboli can be considered ESUS as well, if no other cause, such as carotid disease, AF, or giant cell arteritis, is found.
According to the definition of stroke endorsed by the AHA (Stroke. 2013;44(7): ), strokes include infarcts of the brain, spinal cord, or retina, all of which are considered nervous system tissue.

25. 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

26. FAQs
Question: Subject was diagnosed with cancer after randomization— what does the study team need to do?
Answer:
Report per usual SAE procedures.
No need to stop study drug unless a specific clinical contraindication/indication arises.

27. FAQs
Question: If patient was 44 years old at time of ESUS, but is now 45 years old & within 120-day window, can she participate?
Answer:
Must be 45 years of age or older at time of ESUS.
This patient is not eligible.

28. FAQs
Question: Patient was going to SNF where SQ heparin was planned for DVT prophylaxis; could patient be enrolled?
Answer:
ANY anticoagulant is on forbidden meds list, so if patients are receiving prophylactic-dose SQ heparin, they could be consented but could not be randomized until off anticoagulant.
In this case, PI was able to talk to SNF and convince them that SCDs were a reasonable standard of care for DVT prophylaxis, so patient was able to participate and was successfully randomized.

29. FAQs Question: Can we randomize over the phone and ship study drug?
Answer: Not allowed per protocol because would not be able to reliably check vital signs (esp. BP) and ensure that meds would arrive in time.

30. FAQs
Question: Is a patient eligible for consenting if they have infarcts in the left insula and right hippocampus plus left ICA stenosis?
Answer: This stroke would count as ESUS since the ICA stenosis could not account for all the infarcts.

31. FAQs Question: Is intracranial imaging required before consenting?
Answer: Yes, some kind of intracranial imaging is required to rule out >=50% stenosis and establish the diagnosis of ESUS.

32. ARCADIA Pharmacy Reminders
A new version of the site pharmacy manual was sent out this week. We are now on Version 8. If you have not sent that to your pharmacy team please do so.
More detailed instructions about randomization and dispensing process
Information about the packing slip
BMS temperature excursion form with study drug Lot numbers
Remind pharmacy team that when study kits are shipped to your site they need to be “accepted” in WebDCU™ before they are able to be dispensed.

33. ARCADIA Core Lab Reminders
Core lab tubes must be labeled with the Subject ID and the date
Don’t forget to include a copy of Form 503 v1: Biosample Collection/Shipping
Daniel will be reaching out to all sites who have tubes expiring at the end of the month.
If you have any of these tubes he will be shipping replacements.
The WebDCU system will automatically notify the Core lab to ship 4 additional kits to your site when your site is down to 2. If you have a high volume and need more than 4 kits please reach out to the core lab.
For Core Lab Questions call the CALM Lab at: (212) or

34. ARCADIA Regulatory reminders & updates
If you edit your Delegation Log (DOA) in webDCU™ we need to submit the changes to the CIRB as an administrative amendment.
Before we can submit this amendment you must upload the for the new personnel. StrokeNet COI
New study team members should not conduct study activities until the CIRB approves the DOA change.
Please try to batch your personnel changes to avoid multiple amendments.

35. ARCADIA Study Payments
Everyone is working hard and we want to get invoices out for the enrollments and screenings that have been done.
Please verify that all of your CRFs for a visit have been completed, saved and submitted.
For your enrolled, but not eligible subjects be sure to enter the end of study form.
Filter for any outstanding rule violations or DCRs.

36. ECG and Echo Core Reminders
ECG- be sure to de-identify the ECG before you upload it. If it is sent back to you please try to respond as quickly as possible since the ECG will not be released to the Core to read until it is approved by WebDCU. We don’t want you waiting longer than necessary to find out if you subject qualifies.
Echo- On the CRF there is a new question about what type of Echo that was done. TEE, TTE or both. If you answer TEE you will not be able to enter a measurement for A-P diameter.

37. Database Changes
F505 Echocardiogram Collection: There is a new question on this CRF about what type of Echo that was done - TEE, TTE, or both. If you answer TEE you will not be able to enter a measurement for A-P diameter.
F148 Questionnaire for Verifying Stroke Free Status: This CRF will soon be removed from the CRF Collection Schedule. You should still use this questionnaire to serve as a prompt, but you will no longer be required to enter this data into WebDCU. The document will remain in the study book to serve as a source document.

38. Database Changes
F511 Follow-up Form: Checkboxes will be removed and changed to individual questions. For items that were checked, the data will be transferred to the relevant question and ‘Yes’ will already be selected. For items that were not checked, you will need to either select ‘No’ or leave blank if unknown and respond to the warning.

39. Database Changes
F112 Concomitant Medications: This CRF will soon be archived and no longer available on WebDCU. Some sites have received s asking that they verify the data on F288 with the data on the F112 forms for that subject. Please try to do this as soon as possible and let me know when it has been completed.
Please remember to update and submit F288 Concomitant Medication Log at each visit
49 Month and End of Study Visits have been merged and renamed as ‘30 Day Post Study Medication Termination & End of Study’ Visit
Please remember that for this visit F511 should only be completed 30 days after the date study medication was terminated

40. Who to Contact?
Erin Klintworth at NDMC When to contact: If you have WebDCU-related DOA or regulatory database questions Faria Khattak at NDMC When to contact: Any other WebDCU-related or CRF-related questions
Holly Pierce at NDMC
When to contact: Any other WebDCU-related or CRF-related questions
Jocelyn Anderson at NDMC
When to contact: Any other WebDCU-related or CRF-related questions

41. Screen Failure Logs
This is a friendly reminder that all sites are required to submit a Screen Failure Log by the 10th of the following month.
For example, if your site has no screen failures to report for the month of August 2018, you will still need to submit an August 2018 Screen Failure Log reporting this by 9/10.
To complete a Screen Failure Log for your site, select [Study Progress], click [Screen Failure Log], select August 2018 Screen Failure Log, click [Edit Record] and answer all questions.

42. 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