ARCADIA Trial - Hooman Kamel

October 27, 2021

ID7082

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00:00Neurology and euro science at Wild
00:02Cornell medicine, and he'll be
00:04speaking about the Arcadia Dr Houma.
00:07Hi I started to see you.
00:09Hi thanks for having me
00:11excited to part of this.
00:13I was gonna talk a little
00:15bit about the Arcadia trial.
00:18Let me just see you know as
00:20everyone seeing my PowerPoint here.
00:26Yes, we can see
00:27all right, probably so yeah.
00:27So I'm I'm representing the the Arcadia
00:31piece here and we thought we would talk a
00:34little bit today about a couple of things.
00:37One is sort of how we got from
00:40idea to trial and then some.
00:43Some lessons we've learned in
00:45conducting the trial, but obviously
00:46you know if there's any questions,
00:48please feel free to interrupt and I'm,
00:49you know we can.
00:50We can chat about a lot of different things,
00:51but based on.
00:53Based on sort of the invitation of the topic,
00:56we thought these would be helpful.
00:59So the first thing I think to to,
01:01uh, you know to maybe talk about
01:03is how if you have a trial idea
01:06and you and you wanna get you know,
01:08support and funding.
01:09And it's not just funding right?
01:10You need to get the buy in.
01:11You need people to want to participate
01:14in your trial and helping you
01:16know sort of help make it happen.
01:19How you know how?
01:20How do you build enthusiasm for your idea?
01:24You know Kevin just talked about some of
01:25the ways we approached it and inspire.
01:27There's a lot of different ways to do it,
01:29I think.
01:29You know you can talk about a
01:31compelling clinical question.
01:32There's two strategies we don't
01:34know which ones better you can
01:36talk about a patient group.
01:37That's a very high need and and that
01:40you know you want to try different
01:42things because the current therapies
01:44just aren't working well enough.
01:46There's lots of ways to do it.
01:48One thing that I think that
01:49we used in our in Arcadia,
01:51and that sort of just happened
01:53organically is that we were
01:55able to sort of hang hang.
01:57Our idea on this like pretty easy like.
01:5930 second pitch that I think
02:01got people people excited.
02:02There was like a a concept about it
02:06and you know we we started first by by
02:10pointing out some of the gaps in our
02:13in the prevailing theory of a fib and stroke,
02:16and we pointed out that there's a lot
02:18of literature coming out that didn't
02:20really make sense under the old model.
02:23You know,
02:23if you if you accepted this idea that
02:25you needed the atrial fibrillation,
02:27that it wasn't necessary, or.
02:29For thromboembolism for
02:31cardiac embolism to occur,
02:33there were a lot of things
02:34that didn't make sense.
02:35You know why?
02:35Would only 6 minutes of a fit today
02:37called a stroke a few months later?
02:39Or why would in some cases they fit,
02:42appears for the first time after the stroke,
02:44even though there was no?
02:45You know,
02:45even though patients would be monitored
02:47for a pair before their stroke,
02:48there were some some science
02:50coming out about that why,
02:52you know?
02:53We keep looking for a FIB and and don't
02:55always find it in these patients,
02:56so we we were kind of pointing
02:58out some of these inconsistencies.
03:01And and then we also brought
03:03together a bunch of
03:04different studies that some of which
03:06we had done, some of which had other
03:09people had done including decades ago,
03:11and and sort of pointed out that
03:13all these different studies,
03:15even though they weren't
03:17explicitly about this topic.
03:19Were were, you know,
03:21should only relationship between
03:23markers of underlying abnormal atrial
03:25substrate or atrial cardiopathy and
03:28stroke independent of a state or even in
03:31patients without faith it and and that
03:33if you if you sort of thought about it,
03:35all of this was consistent with this
03:38concept that maybe you know instead of
03:41needing to go through this pathway of a fib,
03:44you can actually have cardiac
03:47embolus and left atrial.
03:49Probable embolism sometimes occurring
03:52even without a triple relation
03:55before and I think this kind of
03:58conceptual shift we're saying,
03:59hey, we have this idea.
04:00Look at all this information.
04:02Doesn't this make more sense?
04:03What do you all think?
04:05And and then you know if that's true,
04:07you know then this,
04:09then this trial would make sense.
04:10Would be a good way of testing that idea,
04:13and specifically,
04:14you know we know anticoagulation
04:16works for preventing stroke in a FIB,
04:18but you know,
04:19wouldn't it also intuitively
04:20work if you have this?
04:22This other pathway coming from
04:24the same left atrial substrate,
04:26and I think that that really helped
04:28us get a lot of enthusiasm both
04:30in the you know concept synopsis
04:32stage at the peer review stage,
04:34and then I think crucially,
04:36even afterwards when you were,
04:38you know,
04:39trying to get sites on board and
04:41get sites to be committed to helping
04:44to recruit and and enroll patients.
04:47So I think that's something to
04:49think about is, you know,
04:50how do you take your idea?
04:52And and put it in a way that you can
04:55like explain very quickly and and
04:57people can kind of synthesize a lot
05:00of information under a pretty simple catch.
05:05All kind of concept.
05:06So I don't know if I'm making sense,
05:08but I think that I'd be happy
05:09to sort of chat more about this,
05:10but I think that was really
05:12helpful to us as we were going
05:13through this whole whole process.
05:15It also helps you kind of center
05:17what you're trying to do with your
05:19trial terms of design and responding.
05:21Some of the critiques, etc.
05:24And then you know,
05:25obviously we we had some pilot data
05:27that will long strip and Mitch Elkind
05:29and others had had a David Torch.
05:32While we're on this paper
05:33suggesting that you know this idea
05:36that anticoagulation would help.
05:38Wasn't just, you know, conceptual.
05:39We actually had some compelling data
05:41from the worst trial to support dot,
05:44so that was very helpful.
05:46So turning to like the other key
05:48thing that I think really helped
05:49us get through the the concept,
05:51you know,
05:52sort of a trial proposal stage and
05:53actually also with conducting the trial,
05:55is this idea of team leadership
05:58or team science.
05:59You know, I,
05:59I think it's been crucial.
06:00We both for aspire, you know, Kevin oh,
06:02Kevin and I working together for Arcadia
06:05with Mitch Elkind and David terse, well and.
06:09Will Longstreth for for whom there's,
06:12you know, will likes to kind of hide in
06:14the Internet shadow, so I don't I don't.
06:17I've actually only seen one
06:18photo of him, but anyway,
06:20this is will he likes his privacy.
06:22So you know, we've been a great team.
06:24We put together this very complicated
06:26looking algorithm for our grant proposal
06:29that in practice has worked really well.
06:31There's a lot of input,
06:33a lot of different perspectives.
06:35We have these weekly trial
06:36Operation committee meetings.
06:37There's a lot of discussion, but I think.
06:40Ultimately, it helps to filter things and
06:42it's it's been it's been very effective.
06:44So even though we got a little bit
06:45of pushback from from a stroke,
06:46net reviewers.
06:47But when we submitted our grant
06:48about the complexity of this,
06:50I think it's worked well given the
06:52the team and and the relationship.
06:54So I definitely advise doing this as a team.
06:58It really helps with a lot of the sort
07:01of stressful points and the workload
07:03and plus it's just great to work with.
07:05You know people that you you respect.
07:08Uhm, and then you know,
07:10obviously even the sort of national
07:12P eyes that are proposing the idea
07:15you get embedded in this larger team.
07:17That's been just great to work with.
07:19You know the NDMC, the NCC,
07:22we have the Arcadia CSI,
07:23ancillary studies with this great
07:26team joining us.
07:27We have all sorts of cores or measuring
07:29our biomarkers and then and then.
07:31Most recently we added a Canadian
07:34coordinating center with some
07:36some old sort of colleague, Jeff.
07:38Julie and David Glass on a Mike Sharma.
07:40So that's been really great too so I
07:42think the team part is really key.
07:44It makes it more fun.
07:45It makes it more robust even though
07:48there are more kind of coordination
07:50costs so to speak.
07:51I think it's I think it's worth.
07:54And then persistence.
07:55I mean, if you if you're trying to fund,
07:57you know, get a trial through this required.
08:00Everyone told me that and and
08:02I'm sort of really living it.
08:04You know,
08:04I remember I got married in November
08:062014 and like I think right this
08:08the weekend before my wedding.
08:09I before I sort of traveled down to Austin.
08:13I sent off the first email to Claudia
08:15and Scott with the concept synopsis.
08:17That was November 2014.
08:18We submitted the first grant and you know
08:21a little less than a year later than the.
08:24The RE submission the notice of award.
08:27We got our first site in February
08:292018 and then it took some time to get
08:31up to the you know full complement
08:33of sites were now a 2/3 recruitment
08:35were hoping to finish recruitment
08:37by the end of 2022 and have the
08:40sort of trial end in June 2024.
08:42So literally a decade long
08:44long journey so I
08:45think that's just to be to be expected.
08:48It's quite a long road.
08:51I other tips, I think just having
08:53some sense of grounding about you
08:55know what you're trying to do because
08:58the the number of critiques you will
09:00get a number of ideas will be large.
09:03You know our our initial grant submission.
09:05There were eight reviewers.
09:06They all had great ideas,
09:07but some of their ideas were literally
09:08contradictory to each other.
09:09How do you navigate that?
09:11If you have to have some sense
09:13of grounding and and realize that
09:15you're not going to make everyone,
09:17it's not that you're going to make
09:18everyone happy, so you can't.
09:19You can't accommodate all the ideas.
09:21Some of them are just going to
09:23be mutually incompatible,
09:24and that's that's fine.
09:25You just have to make a choice and
09:27and trust that you're you know that
09:29that you sort of know the the field
09:32and then you're gonna do the right thing.
09:34Although it's obviously very,
09:35very stressful, 'cause you worry that
09:37maybe you're not making the right choices,
09:38but at some point you have to have
09:41some some degree of grounding.
09:43And then but then,
09:43I think it's really key,
09:45you know.
09:45So you have this sense of grounding.
09:46You know the overall destination
09:48you want to go to,
09:49but I think it's really important for
09:52a couple of reasons to be flexible
09:55and adaptive and how you get there.
09:58The first reason, I think,
10:00is that hey you will,
10:01you will get valuable feedback
10:03from your sites.
10:03They're there, they're local,
10:05they're they're dealing with the patients,
10:06they see what's going on,
10:07and so they will send information to
10:09you that you wouldn't necessarily
10:11have at your disposal.
10:12And it's good to listen to that
10:14and and act on it,
10:16even though it may be kind of inconvenient.
10:19But but act and modify your
10:21protocol as needed.
10:22Until,
10:22I think strengthened the trial to
10:24do that and make a more robust.
10:26But also it helps to generate
10:28enthusiasm for your trial,
10:30because it really ideally should
10:32be a communal experience.
10:33And I sort of, you know,
10:34credit Walter Kernan for for this.
10:36For this sort of phrasing it this way,
10:38but it's really.
10:39I mean, people are not doing.
10:42You know,
10:43being site investigators in multicenter
10:45trials for the money, right?
10:46They're doing it out of a sense of
10:48service out of being part of science.
10:49It's exciting. It's fun.
10:51Yeah,
10:51I feel that way being part of
10:53other peoples trials like it's fun
10:55to to see cool trials happening
10:56and you feel like OK,
10:57we enrolled X number of patients.
11:00You know it feels rewarding.
11:01So you want to harness that and promote
11:03that and and take advantage of it.
11:05So I you know,
11:07as I was thinking about this.
11:09Talk today,
11:10I realized,
11:11like I really missed the in
11:13person investigator meetings and I
11:14think the zoom is just it's not.
11:17It's a poor substitute and I
11:19put these like a
11:20little PowerPoint icon a palm trees
11:23here because I remember our last Arcadia
11:26investigator meeting at ISC in Honolulu.
11:29I think it was 2019 and I just remember
11:33what a great sense of camaraderie this was.
11:36It was sort of one of these adjunct
11:38investigator meetings at ISC.
11:39But a lot of the cipes were there.
11:41We were having, you know,
11:43having beers and just chatting and
11:44people will come up with their ideas.
11:46And I'd say oh that's a great idea.
11:47We should think about that.
11:48It it really?
11:50I think promotes a sense of camaraderie
11:52that we're all doing this together,
11:54and people feel like they have
11:55a voice in the trial.
11:56So I think that I don't know.
11:58I, I really think that in person
12:00stuff is better.
12:01But even even without that,
12:03just meeting with your sites regularly,
12:05asking them how it's going, hearing them,
12:07listening closely, you know and and
12:09incorporating some of that feedback,
12:11I think that's been very helpful for us.
12:13You know, in Arcadia,
12:15Rebecca Aragon, our project manager,
12:16has been amazing at this.
12:17She's been having these calls
12:19with sites periodically.
12:21One of the eyes, you know, dials in,
12:22but really Rebecca kind of leads
12:24the session and she's so good about,
12:26you know, listening and point things
12:28out and having having suggestions.
12:30I think all of these things.
12:32Are really important for
12:34making it a communal project.
12:37We spoke with project managers.
12:38They absolutely crucial
12:39our first project manager,
12:41Irene Ewing,
12:42really helped us launch the study.
12:44Sort of single handedly.
12:44She was.
12:45She was great and and and then now we
12:47have Rebecca Aragon and Pam Plummer who
12:50are a terrific team and they're really.
12:52I mean, they're the heart and soul.
12:53They're doing like 90% of the of the
12:56work now of of making this happen,
12:59so I think that's a really key thing.
13:01And then you know.
13:03Lastly, I just wanted to put
13:04out this idea that you know.
13:06Once a trial gets going,
13:07it it really,
13:09it just requires constant
13:11attention and tending to.
13:12It's not like OK,
13:13it's going and it's in autopilot
13:15and I don't mean just the idea of
13:16like oh you have to constantly,
13:18after cheerleading for the trial to to,
13:20you know, get people to recruit.
13:23That's a given,
13:23but I'm just talking about the
13:25fundamental give to basically be
13:27periodically going down to the
13:29basement and checking on the boiler
13:30and checking on the plumbing because
13:32it things breakdown you know,
13:34especially with a trial like.
13:36Arcadia where I think we have a
13:39relatively complex protocol there are,
13:40you know,
13:41there's been frequent changes
13:42for a variety of reasons,
13:44and so you know making sure
13:46sites are staying on top of
13:47those and aren't overwhelmed,
13:49especially when they it's not
13:51the only trial they're doing.
13:53There's been a lot of staff turnover,
13:54especially recently with COVID,
13:55and so you lose this kind of
13:58implicit learning where you
13:59know if you enroll in
14:00a trial a few times, you kind of
14:02get some of the basic stuff down,
14:04and you maybe don't have to
14:06refer to every line of the mob.
14:08But then when a coordinator leaves,
14:09you lose that, and it's like
14:10it's starting from scratch,
14:11and some of this stuff is almost
14:13like a living memory bank and and
14:16you have to keep refreshing that
14:18on webinars on calls with sites,
14:20because the same things keep
14:22happening over and over.
14:23If you don't,
14:24there's definitely fatigue among
14:26the trial staff and patients.
14:28And what can you do about that?
14:30And then you know all of this is
14:32happening in the context of what
14:33I would call a distributed system.
14:35You know it's a very American thing.
14:37It's a federal Federated system like
14:39you're not directly in charge of anything,
14:41right?
14:42You're sitting here.
14:43You have our CCS and you have sites.
14:46And I actually think overall it's
14:48a strength because you can sort
14:50of put some parameters and say
14:51in general we want patients with.
14:53Esis and and then you can kind of
14:57trust that sites are are figuring
15:00out how that works in their system.
15:02You know,
15:03like maybe one site is getting CT angiograms,
15:05another side gets MRI angiogram somewhere
15:08else gets ultrasounds and T CD's.
15:10You know it doesn't matter so
15:12much as long as it's sort of
15:14being done at some level,
15:16so I think it's it's.
15:17It helps you be able to function
15:19in the in the context of like
15:22a multi multi state trial,
15:24but obviously also has challenges
15:26'cause sometimes you feel like you're
15:28flying blind and how do you deal
15:30with some of the variation and and
15:32it takes more work 'cause you have
15:34to kind of go site to site to do things.
15:36So I think these are some of the
15:38some of the challenges but overall.
15:40I think it it it.
15:42It's actually helpful for for doing
15:44some of the things we talked about,
15:46like engaging with sites and
15:48I think that's all I've got.
15:50So I'll stop there and see if folks
15:53have questions or thoughts you
15:54know we'd love to kind of discuss
15:56what what you all think about this.
15:59Thank
15:59you so much, woman, uh,
16:01these were great insights,
16:03specially for people like myself
16:05and others who are in the process of
16:09submitting multicenter studies for funding.
16:13So thank you so much for this.
16:16I have a question, you know,
16:18as a junior investigator,
16:21submitting UM for a multicenter study.
16:25What were important,
16:27like unexpected challenges?
16:29Just as a heads up, you know,
16:32for me, if the study moves forward,
16:36were there any unexpected challenges
16:38like important sort of COVID?
16:41Obviously, yeah, that you encountered,
16:45that would. You know, be UM,
16:48definitely important, uh, uh.
16:50You know, keep in mind,
16:52as the study moves on.
16:55No, absolutely I, you know,
16:56we definitely had our share.
16:57I, you know. So first of all,
16:59with the I think from the concept
17:02synopsis 2 to the first submission.
17:04I mean, there was a usual give and
17:06take like our our initial proposal was
17:08enrolled like 4400 patients like enroll,
17:10randomized everybody with pieces and and
17:13people shot that down pretty quickly.
17:16So that's fine, we adapted.
17:18And then the the the you know grant
17:20one in the first time it was OK.
17:23But then on the second submission
17:25a there there was like literally
17:27this down to the wire issue about
17:29whether we were going to get study
17:32drugs supplied by VMS Pfizer or not,
17:34and that was incredibly stressful because,
17:36you know,
17:37we had two sets of budgets basically
17:39and and you know it was a huge $4
17:41million line item and and so not
17:43knowing which way we're going to go,
17:45what will we have to cut?
17:47I think we would have had to make
17:48really substantial cuts that would have
17:49kind of actually impaired the trial.
17:51And then we per patient reimbursements
17:53so that. I think just be on your toes.
17:55You have to really get good at
17:57the budgeting and the finances
17:58because it's it's part.
17:59It's very intricately tide into the
18:01success of the of the trial, right?
18:03So I think that's the first tip
18:06and then just you know personnel.
18:08I mean we, you know, I renewing was amazing,
18:11and in retrospect I think all along we
18:14should have had two project managers.
18:16But I think we were just,
18:17you know, everyone was learning.
18:19He kind of took it on herself
18:21for a long time,
18:22but I think frankly it was like it was
18:24too much and and so then finding out
18:26that Irene was low leaving and having
18:28to find other project managers was a
18:30very stressful time because she, you know.
18:33Obviously the project managers
18:35do a lot of the day today.
18:38So I think.
18:38I don't know how you plan for that,
18:41but I think having two project
18:42managers makes a lot of sense to
18:44provide some some kind of buffer.
18:45In case you know something happens.
18:48Those were the big ones.
18:49I'm trying to think of other, you know,
18:50and then the other one was we were,
18:52you know, we were operating the
18:53context of these other trucks.
18:55Yeah, and respect.
18:57And so how do you know?
18:59How do you prepare to respond?
19:00If it's positive it's negative, you know.
19:03How do you pivot that?
19:04That was definitely a big challenge.
19:06I think staying you know
19:08absolutely on top of.
19:09The field and not only in
19:11terms of what's published,
19:12but also like trials that are on the horizon,
19:14and you'd be surprised because,
19:16you know, there's clinicaltrials.gov.
19:19But frankly,
19:20it's it's a little hard to navigate, right?
19:22And so one way I found that's
19:24useful from knowing about trials
19:25and the status of trials actually
19:27is just word of mouth,
19:29because there are trials that you know,
19:31I, I thought were happening and
19:32then you talk to people who know
19:34people who know being there,
19:35like I actually got trial to Scott,
19:36struck down for lack of enrollment.
19:39But you know, it's like there's some.
19:40Be published, public announcement or or
19:42a paper you know publishing this trial
19:45stock so I think just just you know,
19:48networking and being sort of a
19:51tightly embedded in your field
19:53is is helpful for them. Thank
19:56you so much, that's very helpful.
19:58I don't think there are any other questions.
20:01Again, if there anyone has any questions
20:04for Doctor Kamal, please reach out.