ARCADIA-CSI Trial - Maarten Lansberg and Ronald Lazar
October 27, 2021ID7077
To CiteDCA Citation Guide
- 00:00To introduce you and we will
- 00:03be hearing about Arcadia,
- 00:05CSI and ancillary study of
- 00:07the parent trial Arcadia,
- 00:09which aims to determine the effect
- 00:11of anticoagulation on poststroke
- 00:13cognitive function and incidents of
- 00:15silent infarcts representing Arcadia,
- 00:17CSI or Doctor Martin Lansberg
- 00:19and Doctor Ronald Lazar.
- 00:21Dr Lansberg is professor of neurology
- 00:23and neurological sciences at
- 00:25Stanford University Medical Center.
- 00:27Dr Lazar is professor of
- 00:30neurology and neurobiology.
- 00:31At University of Alabama at
- 00:33Birmingham School of Medicine.
- 00:34Thank you.
- 00:36Thanks Richard for the introduction
- 00:38and good morning everyone,
- 00:40and I wanted to share a little bit
- 00:43of what we've learned in setting up
- 00:45an ancillary study today and then a
- 00:48little bit of background on on on
- 00:51the silent infarcts after stroke.
- 00:53And then Ron will be talking
- 00:55mostly about cognition so.
- 01:02Background is that in full 2017 we
- 01:07were finishing up to diffuse 3 trial.
- 01:10It had stopped early and.
- 01:14After the Dom trial had finished
- 01:17enrollment and we had to take an
- 01:21early look at our data and at that
- 01:24point we wanted to use the funds of
- 01:27diffused three to continue studying
- 01:29large for patients with the remaining
- 01:31funds that we had in the study,
- 01:33but that that was not an option because
- 01:36we had to put in a new proposal for
- 01:40the diffuse for large course study,
- 01:42we couldn't use the unused funds and then.
- 01:45Talking to Scott Jennings at that
- 01:47time got some good advice and
- 01:49sort of like off the cuff said,
- 01:51well, you know,
- 01:53sometimes these ancillary proposals and have
- 01:55a better chance of getting funded and so.
- 02:00I, I think around the same time,
- 02:02or maybe at the same meeting Kevin
- 02:06and I were discussing various trial
- 02:09ideas and one thing that came up
- 02:12was what about the Arcadia trial?
- 02:15And they're not doing any
- 02:17imaging in the Arcadia trial.
- 02:19Perhaps we should think about an
- 02:21ancillary study to the Arcadia trial,
- 02:23and then, if we're doing imaging.
- 02:25And what about Viet being
- 02:27interested in cognition,
- 02:28but about also looking at cognition and?
- 02:32And that's how the idea was born, uhm?
- 02:37And we talked to the Arcadia trial P
- 02:39eyes to see if they would be supportive
- 02:41of this ideas and and they were.
- 02:44And then we were lucky to assemble a team
- 02:47of really outstanding experts in cognition.
- 02:51Wrong loser will be talking in
- 02:53in a few minutes. Imaging marks.
- 02:55Winter Market Center radiologist
- 02:58and statistics.
- 02:59George Howard,
- 03:00who is now spent his whole
- 03:02life looking at them.
- 03:04I have to give Myologie in statistics
- 03:06in stroke and come together with their
- 03:10Arcadia trial pies we got on the phone
- 03:14weekly to get a proposal written.
- 03:17And to our vision was to get
- 03:19large scale data of the effect
- 03:22of anticoagulation on two things,
- 03:24silent infarction, cognitive decline.
- 03:25And we thought the results will
- 03:28be important regardless of the
- 03:30results of the parent trial.
- 03:31That would provide deeper insight in
- 03:33the incidence of silent infarcts,
- 03:35the slope of post stroke,
- 03:36cognitive decline,
- 03:37and the relationship between these two,
- 03:40and that it would set the stage for
- 03:43future trials to prevent both silent
- 03:45infarction and post stroke cognitive decline.
- 03:48As Ron will tell you,
- 03:49we felt that you know these are
- 03:52aspects of stroke that are understudied
- 03:55and but very relevant to patients.
- 03:57And so this vision and rationale
- 04:00was really how we try to sell the
- 04:03ancillary study in our brand proposal.
- 04:07And then we come.
- 04:11Little bit of background about
- 04:13RPDR and this apparent trial.
- 04:15It's apixaban versus aspirin for
- 04:17secondary stroke prevention.
- 04:18You'll hear more about that later
- 04:20today from the from the trial piece,
- 04:23and they plan to enroll 1100 patients
- 04:25with cryptogenic stroke and atrial
- 04:28cardiopathy plan of 2 1/2 years of
- 04:30enrollment and a median of three
- 04:33years of follow up.
- 04:34There was no data on cognitive
- 04:36and or imaging outcomes,
- 04:37and So what we would add was these
- 04:39key cognitive in or imaging outcomes.
- 04:41We wanted to integrate seamlessly
- 04:43with Arcadia study visits.
- 04:45So there would be easy for the
- 04:47coordinators and the patients and low
- 04:49barrier for entry and and low burden
- 04:52on the patients and investigators
- 04:54and hopefully high impact if we
- 04:57could show any benefit either on
- 05:00silent infarcts or on cognition.
- 05:04So did bit of background on silent inverse.
- 05:06Very common prevalence 30 to
- 05:0950% in studies instance up to
- 05:1390% every year after TA.
- 05:16And there's data that they
- 05:18accelerate cognitive decline,
- 05:19which shown here in the graph
- 05:21on the left for patients with
- 05:23silent infarcts that follow up.
- 05:25Hey, decline in their cognitive function,
- 05:28and whereas those without
- 05:30a sign in first do not.
- 05:34So next I wanted to go on to sort of,
- 05:37UM, the lessons learned better than
- 05:39to talk about our protocol too much.
- 05:42I thought that for those of
- 05:44you who may be interested in.
- 05:47Designing your own ancillary study
- 05:49that it might be helpful to talk
- 05:51about what we learned in the process.
- 05:53And so the first thing is that it takes time.
- 05:57In October 17, after Kevin
- 06:00and I talked about the plan,
- 06:03we wrote the first draft of
- 06:05the concept synopsis.
- 06:06And two months later, be it in.
- 06:12Submitted this concept proposal to
- 06:14the prevention working group for
- 06:16our first meeting with them and
- 06:18received feedback on the proposal,
- 06:20and we're lucky that after a single review,
- 06:23we were allowed to submit it
- 06:26to an indie S for review.
- 06:28So we put a budget together and then.
- 06:34Updated the concept synopsis a
- 06:37little bit and submitted it to
- 06:40NIS for ESC review in March.
- 06:43In in we got also a positive,
- 06:47so again lucky that we got a
- 06:50positive response from NMDS.
- 06:51They said yes, you're allowed to
- 06:54submit your brand 2 NDS, and so we did.
- 06:57We then went to work and got the
- 07:01grant written and submitted a couple
- 07:042-3 months later, in June 1st, 2018.
- 07:09Half a year later, December 18,
- 07:12we received a summary statement from an end,
- 07:14yes, which looks favorable.
- 07:15But of course you don't know
- 07:17about funding at that point.
- 07:19And February 19,
- 07:21we got funding approved by Council and.
- 07:25We're excited that we could get started
- 07:29thinking about implementing the trial.
- 07:31We wrote our protocol and submitted it
- 07:36for the central IRB in March of 19.
- 07:39And then went to start working on
- 07:42contracts and grants with all the
- 07:44sites and be at the first page in the
- 07:47study about half a year later in November 19.
- 07:50So for those of you who
- 07:53are thinking about this,
- 07:55I think the big picture takeaway
- 07:57is that from first draft of the
- 08:00concept synopsis to first patient in
- 08:03study is two years and that is with
- 08:05everything working flawless Lee and
- 08:09getting funded on the first round.
- 08:13So it in be in for the for the long hold.
- 08:16This is not a it's not even though
- 08:18it's an ancillary study.
- 08:19It's not something that comes.
- 08:22Easy or quickly.
- 08:25A second learning point is that it
- 08:27isn't cheap. Total direct costs are in.
- 08:31It's always a little bit difficult
- 08:33with the stroke net studies to to
- 08:35save what's direct and indirect
- 08:36with somewhere in the five to $6
- 08:38million range for for this study,
- 08:41and I wasn't really aware of that going in,
- 08:44I thought we're adding imaging and
- 08:47we're adding cognitive testing,
- 08:49but we can do that relatively inexpensively,
- 08:52and. It it adds up. Why does it add up?
- 08:56Well for the ancillary study,
- 09:00the way they set up,
- 09:02you need separate contracts with each site.
- 09:05You need to separate curb.
- 09:07There's a separate database at Mercy
- 09:11that is maintained for this study.
- 09:14And so and then of course there's
- 09:17a separate trial management group
- 09:19of the pies and study coordinators
- 09:22to run the trial so.
- 09:25Altogether, and the amount adds up.
- 09:29And then there there's reimbursements
- 09:30to the site.
- 09:34So that is the the second learning point.
- 09:36The third one is that even though we
- 09:38kept eligible eligibility criteria
- 09:39as simple as possible, the inclusion,
- 09:41pretty aware that patient needs
- 09:43to be randomized in Arcadia.
- 09:44Need to be able to undergo MRI able
- 09:47to provide consent in English and
- 09:49score 0 to one on the NH language
- 09:52at the time of Arcadia enrollment,
- 09:54so they could undergo cognitive testing.
- 09:58So I'm very simple.
- 10:00Exclusion criteria really shouldn't
- 10:02exclude too many patients.
- 10:04Get the protocol simple,
- 10:06so simple MRI protocol,
- 10:0850 minutes scanning time 30 minutes
- 10:10total time can use them right from
- 10:13the index stroke at baseline as the
- 10:16baseline imaging study for enrollment.
- 10:18So no really,
- 10:19for most patients just one MRI
- 10:21stand scan at the end of the day,
- 10:24Arcadia participation.
- 10:25And so despite this,
- 10:28enrollment hasn't been easy and we
- 10:30see here that and our involvement
- 10:32is up to 203 which were.
- 10:35Super excited about it and then
- 10:37thanks to all the sites that are
- 10:40here on the call for enrolling.
- 10:42But the parent trial right now has
- 10:45enrolled over 700 patients and we
- 10:47were hoping to enroll about 50%.
- 10:49We thought it would be easy during
- 10:51roll 50% of of total enrollment
- 10:53in the parent trial.
- 10:54So we we had hoped to be
- 10:56somewhere around 375 now.
- 10:58And why are the Orange
- 10:59line is our involvement?
- 11:01The grey line you can ignore for now,
- 11:04so why is it difficult to
- 11:06enroll in ancillary product?
- 11:07Well.
- 11:09One reason is that the parent trial
- 11:12added additional sites and and some
- 11:14of those sites are in Canada and it
- 11:16was challenging for us to go to Canada.
- 11:19That's a small reason,
- 11:20but that's one of the reasons.
- 11:22Two is that we hadn't fully
- 11:26anticipated patients.
- 11:27The number of patients being off
- 11:29study truck in the parent trial,
- 11:30and those are no longer eligible
- 11:33for involvement in CSI because we
- 11:35cannot study our primary outcome.
- 11:37Patients need to consent separately
- 11:39for this ancillary study and
- 11:41and for the parent trial,
- 11:42and that is some additional burden for
- 11:44the patient and some recent patients
- 11:46may not participate and some sites
- 11:49declined to participate because of
- 11:52financial constraints that they're
- 11:53under and making it hard for them
- 11:56to take on both the ancillary study
- 11:58as well as their parents study.
- 12:00Even though we did our very best
- 12:03to maximize reimbursement to
- 12:05sites and and and minimize the.
- 12:09Overhead.
- 12:11And then four lesson is that it's
- 12:13hard to fully integrate with the
- 12:15parent row if the ancillary crowd
- 12:17goes in as a separate proposal
- 12:20by different investigators.
- 12:21So even though we've worked very
- 12:23closely with the Arcadia Pies,
- 12:25and they've been super supportive,
- 12:27we remain two separate study teams,
- 12:29and we have slightly different goals,
- 12:31and rightfully so.
- 12:32The parent trial wants to finish
- 12:34their trial and wants to finish their
- 12:37their enrollment as soon as possible,
- 12:39and so they need to do everything.
- 12:41Like going to Canada,
- 12:43add additional sites to to make
- 12:47sure that their trial is successful.
- 12:50And we are somewhat.
- 12:54We we we are very mindful
- 12:56that by our ancillary trial,
- 12:58we want we don't want to impede
- 13:00their enrollment in any way
- 13:02by overwhelming a patient,
- 13:04who then may say, well, you know,
- 13:06this is just too much.
- 13:06I'm not gonna even enroll in the
- 13:08Arcadia parent trial anymore.
- 13:12And uhm, we, but what I didn't realize.
- 13:15Also, I think going into this is that,
- 13:17uhm, we, we would have separate
- 13:20contracts with each side,
- 13:21so the side would have a contract for Arcadia
- 13:24and they would have a contract for Arcadia.
- 13:26CSI because of that we have
- 13:29slightly different sites, right?
- 13:30Some sites may decide to do Arcadia,
- 13:32but not CSI.
- 13:33And because we have different sites to be,
- 13:36we end up having slightly different webinars,
- 13:39different newsletters. So it is.
- 13:42Uhm, if the ends later study is run by by
- 13:45a different investigative team, it is.
- 13:48We can work closely together,
- 13:50but we cannot fully integrate,
- 13:52which may make enrollment and easier
- 13:55and make it a more cohesive project.
- 13:58And so this is our whole team.
- 14:02We couldn't do it without
- 14:03and I'm going to stop,
- 14:04share and hand it over to wrong
- 14:06to talk more about the cognitive
- 14:07aspects of the study.
- 14:23So I I've been told there's a 5 minutes left,
- 14:26so cognition is usually the caboose on
- 14:28the train, and these presentations,
- 14:29but I've gotten used to it,
- 14:31so I want to thank the the organizers of the
- 14:35Spirit Group today to allow us to present.
- 14:39So I'm going to go through quickly about
- 14:41what we're going to discuss regarding.
- 14:43Your card and assessment scientifically
- 14:46and logistically, and I think the first
- 14:48thing we have to recognize for ourselves
- 14:50that cognition is not one thing.
- 14:52It's a rubric. It's memory, language,
- 14:55attention, executive function,
- 14:57perception, processing, speed,
- 14:58and so when we do a study,
- 15:00whether it's Arcadia, CSI, or any others,
- 15:02we have to ask ourselves if cognitions
- 15:05and outcome was it we're trying to study,
- 15:08and that if we're doing memory when
- 15:10not necessarily doing language,
- 15:11and so we have to be circumspect
- 15:13about what we want to.
- 15:14Pay attention to and.
- 15:15Secondly, cognition is highly
- 15:17sensitive to brain integrity,
- 15:19which means that you don't necessarily
- 15:21need to have a lesion on MRI in order
- 15:24to have an impact on cognition from
- 15:27an intervention or from disease.
- 15:29So we have to tell her the battery
- 15:31to the disease we're studying.
- 15:33If you're looking at focal stroke then
- 15:35you can study language and recognition,
- 15:38factual memory, practice, spatial perception.
- 15:42But if you're looking at multi
- 15:44focal or diffuse disease then you're
- 15:46dealing with more widely distributed
- 15:47functions such as attention,
- 15:49working memory,
- 15:50executive functioning reasoning
- 15:52and processing speed.
- 15:53So whatever you decide to do to choose as an
- 15:56outcome in terms of your cognitive domain,
- 15:59it should match the.
- 16:00Pathology that you're trying to study.
- 16:02So this is a slide from yells oh
- 16:05natural Alexandria Lanski,
- 16:07who chaired the Neurologic Academy Research
- 16:10Consortium on outcomes for neurologic.
- 16:15Effects from cardiac treatment
- 16:17and disease and what I want to
- 16:19point out to you from here,
- 16:21and I participate in this consortium
- 16:23is that we can use cognition either
- 16:26as part of an effectiveness trial,
- 16:28which would be an example of Crest age,
- 16:30where one want to see whether or not
- 16:33restoring perfusion would increase cognition,
- 16:34or it could serve as a safety outcome.
- 16:37You decide where does cognition belong,
- 16:39and sometimes it's going to
- 16:41correlate with the DWI image,
- 16:43and sometimes it's not going
- 16:44to correlate with a DWI image.
- 16:46So we have a wide range of possibilities
- 16:49about how cognition can exist
- 16:52in a cardiovascular trial.
- 16:54Who does the assessment in in these studies?
- 16:56Well,
- 16:57here are four examples that I've used
- 17:00over the years in the study above the
- 17:02amphetamine and hand cognitive recovery.
- 17:04After stroke we use nurses and both
- 17:07registered nurses and nurse practitioners,
- 17:10and accord C,
- 17:11which is the action to control
- 17:14cardiovascular risk in diabetes study.
- 17:16We actually used assistant clinical
- 17:18coordinators at about 50 sites around
- 17:21the United States that we trained.
- 17:23Then in the Sentinel study,
- 17:24which I'll talk about in a
- 17:26second which only had 19 sites,
- 17:28we use clinical notes are
- 17:30neuropsychologists and then for
- 17:31Crest two and Crest H and Arcadia,
- 17:33CSI. We're using centralized telephone
- 17:35based assessment because of the very
- 17:38large number of centers we want to do.
- 17:40If you want to standardize
- 17:42assessment in our judgment,
- 17:44it's best to do it from one central
- 17:46place so we can maintain the quality and
- 17:49and of the evaluations that were doing.
- 17:52So the battery that we're using for KDS I,
- 17:56which is the same as that fircrest
- 17:59two consists of being able to give as
- 18:01many words as possible to FA&S room.
- 18:03But this is a telephone based battery.
- 18:05How many animals can you name in a minute?
- 18:08Your ability to learn 10 words
- 18:10over three trials,
- 18:11a later recall of those 10 words,
- 18:13digit span and oral trail making.
- 18:16So the first question when the when
- 18:18the questions we wanted answered
- 18:19for ourselves is how sensitive
- 18:21is this battery battery in there?
- 18:23In the context of a telephone administration,
- 18:27so using the Crest two data,
- 18:30we compared the Crest data
- 18:33from these tests here.
- 18:36Letter fluency animal naming,
- 18:37word list learning and word list
- 18:40recall to the regards study at 30,000
- 18:43patient population based study of
- 18:45white and not for American blacks,
- 18:47largely in stroke belt and what we
- 18:49simply did is took the score from Crest,
- 18:51two subtracted from that demeans.
- 18:54Regards score in regards to any
- 18:56deviation and calculated Z scores for
- 18:58individuals from Crest two which was
- 19:00joke free and then match for age,
- 19:02sex,
- 19:03education and risk factor and
- 19:06what we found briefly.
- 19:07Is that if you take a look at the
- 19:09expected distribution which is regards
- 19:11and you compare the results across
- 19:14Crest 2 for Animal naming letter F only
- 19:16wordless learning and word list recall.
- 19:19You can see that there has been
- 19:22relatively little impact for
- 19:23naming for letters and and animals.
- 19:26Some impact on on on learning,
- 19:29but a significant decline in wordless delay.
- 19:32And these are data that coming out in stroke.
- 19:35So did this shows that there
- 19:37is some sensitivity to.
- 19:39To a telephone based battery from
- 19:41from at least carotid disease,
- 19:43which of course is not the same
- 19:46mechanism for Arcadia CSI,
- 19:47but the impetus in in looking at
- 19:50sound infarction that we could use.
- 19:53Comes from the Sentinel data,
- 19:55where we looked at how patients
- 19:58perform them cognitive testing before
- 20:00and after a Tavern and what we have
- 20:04here from 189 patients is this is
- 20:07the log transformed lesion number.
- 20:09This is disease score change before and
- 20:11after Taver 0 represents no change,
- 20:14a better score,
- 20:15a worse score and you could see
- 20:17the more the greater number of
- 20:18lesions the worst of cognition is
- 20:20and if you look at lesion volume.
- 20:22Essentially you get the same fining,
- 20:24so we know that in the setting of silent
- 20:28infarction in the absence of stroke,
- 20:30that cognition is a sensitive metric of.
- 20:34Of a silent infarction here.
- 20:38So in a in a brief one New York minute,
- 20:42that's kind of the way we're
- 20:44we're attacking cognition in the
- 20:46setting of sound infarction,
- 20:48and we'd be glad to answer any
- 20:50questions that you might have. And I'll.
- 20:53Thank you very much.
- 20:55Doctor Lutheran in doctor plants Berg,
- 20:57I believe there is a question
- 20:59in the chat by Shaggy.
- 21:03Great point about the consent
- 21:05process of ancillary studies.
- 21:07What is the barrier of having
- 21:09Arcadia CSI consent included
- 21:11in the Arcadia consent?
- 21:14And I just answered in the chat also,
- 21:17it's my understanding and perhaps there's
- 21:21people on the call from from Cincinnati
- 21:23who can answer this even better.
- 21:26That because the answer studies he
- 21:28knows are completely separate study,
- 21:29that is has its own review process
- 21:32in the CRB that separate consent is
- 21:35required and that it is logistically
- 21:38just difficult to integrate it.
- 21:40In in the Arcadia consent form,
- 21:42partially also because Arcadia patients,
- 21:44probably, you know,
- 21:45a lot of patients are consented in Arcadia,
- 21:48who will never get randomized,
- 21:49and we only look at the randomized patients.
- 21:53I don't know if Ben Plummer or anybody
- 21:56else has had more eloquent response. So,
- 22:01so Karen Fury asked a really
- 22:03important question about having
- 22:05English consent as a entry criterion
- 22:08for for getting into the study.
- 22:10And that raises a larger issue is
- 22:13because the test battery is also in
- 22:16English and and so I remember when we
- 22:20were going through the process of.
- 22:22The stroke net.
- 22:25Planning group that Ralph Sacco
- 22:27is exactly the same question,
- 22:29how come you don't have Spanish
- 22:31and it is definitely a limitation
- 22:33of our study and will limit the
- 22:36kind of conclusions we get.
- 22:38So try to translate the the battery.
- 22:41We're using that telephone base
- 22:43that came from regards and then
- 22:45into Crest too and and and and CSI.
- 22:47We've been trying to get funding
- 22:50to translate that battery and
- 22:51to validate it and and it's been
- 22:53a complicated process, but.
- 22:55When we have to do so,
- 22:56the limitation is acknowledged.
- 23:00Thank you another question from Walt Kernan.
- 23:03Is cognition a possible outcome
- 23:05for trials intended to gather
- 23:07preliminary data for novel therapies
- 23:09for secondary stroke prevention?
- 23:11If so, how many patients are needed
- 23:12to show typical treatment effect?
- 23:16Well, that time Walter,
- 23:17you always ask the hard questions and
- 23:20we don't have a a good answer to that.
- 23:24So our outcome in in Arcadia
- 23:26CSI is not that different.
- 23:29At the end of four years,
- 23:30but the slope and and so we we
- 23:34will only know at the end of the
- 23:36trial if the slope is separate
- 23:39far enough apart overtime whether
- 23:41or not we can get a treatment,
- 23:43you know that they did that.
- 23:44Martin present from Vermeer,
- 23:45was a population based study.
- 23:47And these patients, probably silent
- 23:49auction for twenty 30-40 years.
- 23:51But in the setting of a clinical
- 23:53trial and you only have two,
- 23:54three and four years.
- 23:56We felt that a solid endpoint of
- 24:00Group A versus Group B at four
- 24:03years would not show a sufficient
- 24:05treatment effect at that time.
- 24:06So for us,
- 24:07slope seemed to be the more
- 24:08attractive way of doing it.
- 24:09Next to best we have right now.
- 24:13You keep up very much, and
- 24:16if there are any other questions,
- 24:18maybe they can be directed
- 24:19to both offline thank you.
- 24:21Will take the opportunity
- 24:22to have a small break.