1. PI and Coordinator Webinar
June 25, 2019

2. Site startup 119 -> 125 sites released to enroll
117 sites currently active
114 -> 114 sites with at least one consent
73 -> 76 sites with at least one randomization

3. Enrollment 895 -> 964 patients consented 220 -> 233 randomized
Increase of 69 in past month
220 -> 233 randomized
Increase of 13 in past month
Overall 0.18 patients randomized/site/month
Overall 233/964 patients consented  24% randomized

4. Top enrolling sites – by # randomized
Consented
Proportion
United 10 35
0.29
Cincinnati 30
0.33
OHSU 9 31
Iowa
Memorial Hermann 8 20
0.40
Penn 7 22
0.32
UF Shands 18
0.39
MUSC 5 21
0.24
Emory
0.23
Kentucky
0.25
MedStar Georgetown 15
OSU Wexner 17

5. Top enrolling sites – by randomization rate
Randomized/Month
Date released to enroll
United
0.72
May 1, 2018
OHSU
0.65
May 3, 2018
Emory
0.62
Oct 23, 2018
Iowa
0.61
Apr 2, 2018
Cincinnati
0.59
Jan 29, 2018
Memorial Hermann
0.51
Mar 5, 2018
Mayo Saint Mary’s
0.49
Jun 21, 2018
Penn
0.47
Mar 30, 2018
UF Shands
0.46
Mar 20, 2018
Barnes Jewish
0.45
Dec 4, 2018
Kentucky
0.44
Jul 11, 2018
Wake Forest
0.43
Apr 16, 2019

6. New randomizers Buffalo General Greenville Hospital System Wake Forest
Sharp Memorial

7. ARCADIA Coordinator Hero
Daniel Burch at Greenville Hospital System in South Carolina
Time flies!
The 120 day post-stroke window to randomize seems like a long time.
Many stroke patients go to rehabilitation facilities, live with a relative temporarily, or even move closer to loved ones after their stroke.
Even though they have signed consent, we need to keep in touch with them to confirm they still wish to continue in the trial and be randomized for the study drug.
We should try to randomize patients as soon as possible within the protocol guidelines.
Sometimes it takes leaving various messages, calling the contacts the subject provided, and even sending letters.
Our coordinator hero kept trying to reach a patient to the very last day and was able to enroll their first patient!
 Thank you Daniel for not giving up!
 Thank you Daniel and Paula Zortea and Greenville Hospital System for such a great start in the ARCADIA trial!

8. ARCADIA Coordinator Heroes
Melissa Thomas/Osama Zaidat at Mercy St. Vincent in Toledo, OH
Blas Garcia-Canga/Frances Caprio at Northwestern
The patient was seen in Toledo and seemed eligible, but lived in Chicago.
The Toledo team reached out to Hooman, who put them in touch with the Northwestern team.
 Thank you for this great teamwork!

9. ARCADIA Coordinator Heroes
Jessica Henry/Richard Zweifler at Ochsner in New Orleans
Gail Cooksey/Anjail Sharrief at Memorial Hermann, Houston
The patient was seen at Ochsner and seemed eligible, but was moving to Houston.
The Ochsner team reached out to PIs, who put them in touch with the Houston team.
 Thank you for this great teamwork!

10. Quick survey: Practice patterns of ARCADIA investigators
 Does your site routinely check BNP or NTproBNP in patients diagnosed with ESUS?
Answer (make sure to read all before responding!)
a. No.
b. Yes, BNP.
c. Yes, NT-proBNP
d. Yes, sometimes BNP and sometimes NT-proBNP
e. Yes, not sure which

11. Quick survey: Practice patterns of ARCADIA investigators
 Does your site routinely check BNP or NTproBNP in patients diagnosed with ESUS?
Please enroll patients regardless of the local result.
Don’t pre-screen ESUS patients by testing the BNP/NT-proBNP first.
The assays differ and results at the site may differ from results at the Laboratory Core.
Only results from the Laboratory Core are used to determine eligibility for randomization.

12. Quick survey: Practice patterns of ARCADIA investigators
Do clinicians at your site measure (or try to measure) the P-wave terminal force in lead V1 in patients diagnosed with ESUS?
 Answer: No
Yes

13. Quick survey: Practice patterns of ARCADIA investigators
Do clinicians at your site measure (or try to measure) the P-wave terminal force in lead V1 in patients diagnosed with ESUS?
Even if you do measure the PTFV1, please enroll the patient regardless of the local read.
The measurements may differ and results at the local site may differ from results at the ECG Central Laboratory (Wake Forest). The reliability of local reads is unknown and they may differ from those at the ECG Central Laboratory.
 Please do not try to pre-screen patients diagnosed with ESUS; instead try to consent all patients meeting criteria for ESUS.

14. FAQs
Question: Are chronic lacunar infarcts an exclusion?
Yes No

15. FAQs Question: Are chronic lacunar infarcts an exclusion? Answer: No.
As long as the acute infarct is consistent with ESUS, then any prior lacunar infarcts the patient may have had would not exclude them.
In many cases, the finding of chronic lacunar infarcts may be based on imaging. Finding prior chronic small vessel infarcts is common in patients with vascular risk factors.
These patients are eligible!

16. FAQs
Question: A patient has ESUS at an outside hospital. The physicians there tell you that the patient had elevated Factor VIII levels. The patient is currently on aspirin.
Is the patient eligible?
Yes No

17. FAQs
Question: A patient has ESUS at an outside hospital. The physicians there tell you that the patient had elevated Factor VIII levels. The patient is currently on aspirin.
Is the patient eligible?
Answer: Yes
If the team does not think that the elevated Factor VIII level warrants open label anticoagulation, then she is eligible. 
Consider repeating levels/hematology consultation if uncertain.

18. FAQs
Scenario: A patient is enrolled in the Multi-arm Optimization of Stroke Thrombolysis (MOST) trial. The trial has three arms: rt-PA + placebo, rt- PA + argatroban, and rt-PA + eptifibatide.
Is the patient eligible to participate in ARCADIA?
Yes No
Maybe

19. FAQs
Scenario: A patient is enrolled in the Multi-arm Optimization of Stroke Thrombolysis (MOST) trial. The trial has three arms: rt-PA + placebo, rt-PA + argatroban, and rt-PA + eptifibatide.
Is the patient eligible to participate in ARCADIA?
Answer: Trick question!
Yes, maybe
Patients in MOST or other acute stroke therapy trials are eligible as long as they are still within the 120-day post stroke window and have met the ARCADIA Inclusion/Exclusion criteria.
MOST of these trials have a 90 day window, so these patients can be eligible!

20. FAQs
Question: A 48 year old black woman has an unexplained left middle cerebral artery stroke while exercising at the gym. She has a history of migraine with visual aura and she has had prior episodes of transient paresthesias with migraines as well. She has mild residual aphasia.
Is she eligible to be consented for ARCADIA?
Yes.
No.

21. FAQs
Question: A 48 year old black woman has an unexplained left middle cerebral artery stroke while exercising at the gym. She has a history of migraine with visual aura and she has had prior episodes of transient paresthesias with migraines as well. She has mild residual aphasia.
Is she eligible to be consented for ARCADIA?
Answer: Yes.
Must use clinical judgment.
Our I/E criteria say: “No other specific cause of stroke identified, such as arteritis, dissection, migraine, vasospasm, drug abuse, or hypercoagulability.”

22. Recruitment redux 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.

23. Recruitment redux
?Eligible

24. Recruitment redux 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.

25. Recruitment redux
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).

26. 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 Rebeca Aragon, Pam Plummer, the PIs, or us at

27. FAQs
Scenario: You consented a patient 3 weeks ago while he was in the hospital, and he is eligible for randomization. He is now being discharged to rehabilitation and he will be released to home in 3 weeks. You set up an appointment with him for randomization one month from discharge. His family ask that he come in for an early appointment, and you arrange the appointment for 8 AM.
Question: Should you register the randomization in WebDCU the night prior to his visit so that you have everything ready first thing in the morning?
Yes No

28. FAQs
Scenario: You consented a patient 3 weeks ago while he was in the hospital, and he is eligible for randomization. He is now being discharged to rehabilitation and he will be released to home in 3 weeks. You set up an appointment with him for randomization one month from discharge. His family ask that he come in for an early appointment, and you arrange the appointment for 8 AM.
Question: Should you register the randomization in WebDCU the night prior to his visit so that you have everything, including drugs, ready first thing in the morning?
Answer: No.
The patient should be on-site and prepared for randomization. Patient and family feelings sometimes change after they leave the hospital. We want to avoid having patients get randomized but not treated. Patients should always be rescreened to exclude and their randomization.

29. FAQs
Scenario: You consent a subject in the clinic after reviewing the case with the local PI. The subject has not had intracranial imaging. The PI orders a CTA, but it has not yet been done. The patient is not eligible for randomization locally by the echo. You answer the appropriate I/E criteria questions and send off EKG and blood for NT-proBNP. For the question (Q09) regarding “Absence of intracranial atherosclerosis causing ≥ 50 percent luminal stenosis of the artery supplying the area of ischemia” you enter “No” since the imaging has not been done yet.
Two days later, you receive a “subject not eligible for randomization” alert.
Question: Might this patient still be eligible for randomization?
Yes No

30. FAQs
Scenario: You consent a subject in the clinic after reviewing the case with the local PI. The subject has not had intracranial imaging. The PI orders a CTA, but it has not yet been done. The patient is not eligible for randomization locally by the echo. You answer the appropriate I/E criteria questions and send off EKG and blood for NT-proBNP. For the question (Q09) regarding “Absence of intracranial atherosclerosis causing ≥ 50 percent luminal stenosis of the artery supplying the area of ischemia” you enter “No” since the imaging has not been done yet.
Two days later, you receive a “subject not eligible for randomization” alert.
Question: Might this patient still be eligible for randomization?
Answer: Yes
Patients should only be consented once the full evaluation for ESUS has been done. In this case, though, the reason that the patient was deemed ineligible was because the brain imaging had not yet been done. The patient did in fact meet criteria for atrial cardiopathy by EKG and NT-proBNP.
Reminder: Check the Study Progress / Study Subject Status area to see if a subject is eligible. Do not base eligibility solely on the alert, which may indicate ineligibility based on a F101 error or missing info.

31. FAQs
Scenario: An ARCADIA participant is an 88 year old woman who keeps all her medication bottles in a bowl and the entire bowl is now missing. A thorough search was done by her family without luck. This was relayed to the study team via her daughter and it is unknown when she took her last dose of study medication.
Question: Can medication be replaced?
Yes No

32. FAQs
Scenario: An ARCADIA participant is an 88 year old woman who keeps all her medication bottles in a bowl and the entire bowl is now missing. A thorough search was done by her family without luck. This was relayed to the study team via her daughter and it is unknown when she took her last dose of study medication.
Question: Can medication be replaced?
Answer: Yes
We can perform a manual override to allow inclusion of patients in this scnerio, but this should be an exception.
It is essential to make sure that patients, many of whom will be elderly and have obviously had a stroke, are provided support, if necessary, to take medications properly.

33. FAQs Question: Who can be a Principal Investigator in ARCADIA?
a) Neurologist
b) Internist
c) Nurse Practitioner
d) All of the above

34. FAQs Question: Who can be a Principal Investigator?
Answer: d) All of the above
A dedicated NP with research and vascular neurology experience could serve as PI, if properly trained and committed to the trial.
All require their CV to be reviewed and approved by the national PIs.

35. Echo reminders
The calculation of the left atrial diameter index is complicated
You do not need to calculate this
Simply enter the LA diameter from the echo report and WebDCU will calculate the LA diameter index automatically (using height and weight)
Expected range: 2 – 7 cm
Shipping echos:
Please send in outstanding echos
We will move to shipping every three months
Reach out to your echo lab to ensure the images are saved in DICOM format and that they are editable.
Only one patient study should be downloaded to each DVD
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

36. REMINDER: Delegation of Authority Changes
Require CIRB Administrative Amendment Submission
You must upload the person’s HSP & COI documents, have them reviewed/approved before we can submit to the CIRB
You must receive CIRB approval of addition, role or responsibility change before these are active
Consider changes needed for new staff, fellows, etc. so as to submit these in a timely manner without making daily changes
Each instance requires the submission of CIRB Administrative Amendments I

37. NEW Site Consent Documents (main v6 & PPv3)
New sites are coming onboard using Protocol v.4.1 and do not need consent form changes
ALL of the sites requiring specific changes have been submitted to the CIRB
Until the CIRB approves your site-specific v6 & v3 consent forms, please continue screening and enrolling using your previously CIRB approved consent forms at your site.
Once the CIRB approves your site-specific main consent form v6 and Pregnant Partner v3, then you are officially working under the new protocol (now v4.1)
If your local IRB needs to review/approve the new CIRB approved consents, your site may not be able to enroll during that review period (depending on your site’s requirements). It will be imperative to submit this to them as soon as you receive it for acknowledgement.
Re-consent each active subject with the newly approved site-specific consent forms as soon as possible (both on & off study drug subjects)
NOTE: Pre-existing sites will need to have your PI sign the Protocol Signature Page for 4.0 AND the 4.1 (as the consent form changes are associated with v4.0)

38. Trial Agreement Amendments
Once the NOA was received at the NCC, Diane Sparks started to work on all Y3 amendments – should be going out by the end of June.
We want to assure everyone that there will not be any lapses as the amendments will have a start date of 5/1/2019 (prev year exp 4/30/2019).
Please continue to enroll and thank you for your patience.

39. Literature update
Ntaios G et al. Carotid plaques and detection of atrial fibrillation in ESUS. Neurology 2019; 92:e
Background: Substenotic plaque (i.e., carotid plaque <50%) may be a cause of ESUS. If so, then patients with ipsilateral substenotic plaque should be LESS LIKELY to have AF detected during follow-up.
Hypothesis: Patients with ESUS with substenotic plaque are less likely to have AF detected during follow up.

40. Literature update Retrospective analysis
777 patients from 3 different registries (Lausanne, Athens, Larissa)
Follow up 2642 patient-years (mean 3.4 years per patient)
Primary outcome: detection of AF; no systematic monitoring for AF
Ntaios G et al. Neurology 2019; 92:e

41. Literature update Retrospective analysis
777 patients from 3 different registries (Lausanne, Athens, Larissa)
Follow up 2642 patient-years (mean 3.4 years per patient)
Primary outcome: detection of AF; no systematic monitoring for AF
Results:
38.6% of patients (n=341) had an ipsilateral substenotic plaque
The detection rate was 8.5% in patients with substenotic plaque vs 19.0% in patients without substenotic plaque.
After adjusting for other factors, presence of plaque associated with ~50 likelihood of detecting AF (adj HR 0.57, 95%CI ).
Ntaios G et al. Neurology 2019; 92:e

42. Ten-year cumulative probability of atrial fibrillation detection in embolic stroke of undetermined source patients with and without nonstenotic carotid plaques ipsilateral to the index stroke
Ten-year cumulative probability of atrial fibrillation detection in embolic stroke of undetermined source patients with and without nonstenotic carotid plaques ipsilateral to the index stroke
George Ntaios et al. Neurology 2019;92:e2644-e2652
© 2019 American Academy of Neurology

43. Literature update Potential implications: Limitations
Substenotic plaque may be causally associated with ESUS
The finding of substenotic plaque may be a reason to pursue more or less aggressive monitoring for AF (i.e., look less hard in those without the plaque)
Patients with substentoic plaque may similarly be less likely to have atrial cardiopathy
Limitations
The incidence of AF detection is high even in those with substenotic plaque (~9% over 3 years).
Study was retrospective
No systematic monitoring for AF or uniform detection protocol (i.e., based on clinical detection)
Patients did not have intracranial imaging for “pragmatic reasons”: may not have all had ESUS
Ntaios G et al. Neurology 2019; 92:e

44. Open mike…

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