ASPIRE Trial - Kevin Sheth

October 27, 2021

ID7081

To CiteDCA Citation Guide

00:00We're good. OK, OK, great.
00:02There are times a charm.
00:04So uhm so uh thanks it's been great to
00:07hear some of the talks from the morning I.
00:10I think one of the things I
00:11was going to say and I'll,
00:13I'll make mine a little bit more informal.
00:15So really, if people want to ask
00:16questions even in in between,
00:18that'll be fine.
00:19One of the things that we did in
00:21inviting our trial pies was make a
00:24request today that they simply didn't
00:27talk about the protocol and the design.
00:29One. I think a lot of us have.
00:31Heard that that you know might
00:33be a little bit, you know,
00:34but what we thought we could do
00:36and I think this is an originally
00:38Lauren Sansing's idea to you know,
00:39to ask him a little bit about
00:41the back story you know and and
00:43and some other questions about
00:45that you don't always hear about,
00:47so I thought I would very much
00:50do that for aspire.
00:52These aren't the things you would
00:53find in the protocol or the lead
00:55up that that might be relevant when
00:56you're thinking about your own trial,
00:58because all of these things they
00:59always do have a back story.
01:01Every little detail,
01:02and the first thing really is,
01:04you know the waste.
01:05One of the things that I think
01:07about at the beginning of really
01:08most of the projects I started is
01:10just don't say the choice of team
01:12but just the team that you either
01:13choose or that you end up working
01:15with and a little bit of both.
01:17And you know I want to just mention
01:19a couple of people, of course.
01:21There are a lot of folks that are
01:24involved in a clinical trial,
01:25but you know,
01:26one of the things that I would say
01:28I think is as many of you know,
01:29I'm a critical care neurologist and you know,
01:33here I was trying to think about
01:35proposing a stroke prevention trial,
01:37so I thought that you know people
01:39might laugh and find that a little bit funny.
01:42Doing stroke prevention is something
01:44that I always wanted to do ever since
01:46fellowship and it just happened to
01:48be that my clinical interests were
01:50mostly in sort of acute neurology.
01:53So a few years ago I before aspire,
01:56you know where it's nice at Yale.
01:58We have sabbaticals every so often
02:00and so I I had a sabbatical and I
02:03used that experience to really think
02:05about how to design and think about.
02:07You know,
02:08doing a prevention trial in a
02:09disease that I did know something
02:11about and was was sort of passionate
02:13about and there was no interest,
02:14real hemorrhage.
02:15And in doing that one of the first
02:19things that I did was reach out to a
02:22colleague who was many of you know who,
02:24Monica Mellow.
02:25As my copii at Cornell,
02:27and I say this with great respect
02:29to everyone on the call.
02:31But you know,
02:31one of the reasons we reached out
02:33and I started working with him
02:35was one because of his, you know,
02:36deep and recent experience in
02:38getting Arcadia off the ground.
02:40Even though it was
02:41hemorrhaging ischemic strokes.
02:42Some of the questions and
02:45practical interventions were
02:46going to be very much the same,
02:48and also because I really thought from our
02:51generation he was really one of the nicest,
02:53smartest people in the field
02:55and so being able to capture.
02:57Both of those things you know
02:58was was a great opportunity.
03:00The other thing that ended up
03:02playing a big role for me.
03:03We've had a lot of folks
03:05in our steering committee,
03:06but just being here at Yale was
03:08being close to Walt Kernan.
03:10And as all of you know,
03:11I mean, I think many of you,
03:12Karen and others were involved
03:13in the IRIS trial,
03:15which was really only one of the
03:17one of the few sort of successful
03:20prevention trials in NIH history,
03:22at least by efficacy outcome,
03:24and you know,
03:25to have that experience was very helpful.
03:27To have in hand and thinking about the
03:29concept but even big picture questions,
03:31I remember one of the things that
03:33Walt asked me at the beginning was,
03:35you know, do you really want to commit
03:37potentially 7 to 10 years of your life?
03:39You know,
03:39before you embark on an endeavor like that,
03:42you gotta really think about that.
03:43So that was very helpful.
03:45The 4th person I haven't put here and
03:47that's because she's oftentimes pretty
03:49humble about these kinds of things.
03:52And it is, you know,
03:53if you go to Google pictures,
03:55you really cannot even find a picture of her.
03:57I mean, it's.
03:58Really quite remarkable,
03:59and that and that's Catherine Visco Lee.
04:01So Catherine Viscol is some of
04:03you know that this is the picture
04:05that she did send me of herself,
04:07which in some ways you know it's it's
04:09not not not an inappropriate picture.
04:11I'll tell you.
04:12But Catherine,
04:13this Coley is is not a clinician,
04:16but actually has been involved
04:18in stroke investigation.
04:20You know,
04:20for many many years and I I don't know
04:23if people at Yale even know this.
04:27Sort of having some of these
04:28slides out of order, what's up?
04:30But you know Catherine.
04:33Actually, you know has a CV in some
04:35ways that you know some stroke
04:38investigators would never have, even at
04:40over the course of their whole career.
04:42And you know she happened to have
04:44this rich experience in thinking
04:46about not just conducting the trial,
04:49but analyzing it, reporting it
04:51really doing everything from A-Z.
04:54Not only in these studies that you see here,
04:56but all still in the iris.
04:57Trial and, uh, so that you know, working.
05:01I think with this team from the
05:04beginning was just as much I,
05:06I think as important as the fundamental
05:08sort of scientific question.
05:10So I I just wanted to.
05:11I think this is obvious to everyone,
05:13but just to give a couple of
05:15pieces for how this came together,
05:17I think it's a critical part of how
05:18the trial concepts come together.
05:20You know,
05:21in that context what I would say is,
05:23and there are a lot of people I.
05:24I'm just highlighting a few here
05:26to make a point and make a point
05:29in the context of aspire.
05:30You know, when we were designing,
05:32and as we've been conducting this study,
05:34we've been thinking about
05:35a lot of different things.
05:36As you'll hear about in a minute,
05:37you know what are the right outcomes?
05:39What can we learn about aspire beyond aspire?
05:44You know what are the relevant
05:46outcomes beyond our top line outcomes,
05:48and you can see here, you know,
05:51Lauren Gaido, Alessandro Biffi.
05:53I mean they've all had, I think,
05:55really key pieces of input into
05:56that and really unique perspectives.
05:58You know, we didn't choose,
06:00but you know,
06:01the current chair of the DSMB is Clark Haley.
06:05So as many of you know,
06:07Clark Haley was very involved in the
06:09leadership of the original NINDS TPA trials,
06:12and it turns out that these historical
06:14things become relevant because you know what?
06:18For in a different context,
06:20when they were thinking about when
06:22they were looking at TPA and having
06:24those very early DSMB meetings
06:26for the NDS TPA trial,
06:28they really had to think about this
06:31balance of efficacy and hemorrhage,
06:33bleeding and clotting in a very.
06:35Sort of,
06:35you know,
06:36in an environment where they didn't really
06:38know that much from a clinical context,
06:40and without you know sharing any sort
06:44of insight information from the trial,
06:47I think everybody would understand that.
06:48You know when you're thinking about aspire,
06:50not just in the design,
06:52but as the study goes along and
06:54people start having endpoints clotting
06:56endpoints or hemorrhaging points.
06:59These issues really come to the fore.
07:01I'll give you one concrete example.
07:03Oftentimes in a trial like this people will.
07:05Think about having a hemorrhage
07:07as a safety outcome.
07:09Well, you could ask why, why should it?
07:12Why shouldn't hemorrhage only
07:13be a safety outcome?
07:14That's a that's if you think
07:16about safety as active harm.
07:18But if you think about ischemic
07:20stroke as sort of
07:22passive harm or passive safety endpoint,
07:25then then ischaemia is can also
07:27be considered a safety endpoint,
07:28not just an efficacy endpoint.
07:30And believe it or not,
07:31some of these kinds of issues, really,
07:33as we've learned during the course of
07:35the trial, they're not completely baked.
07:37They really are something that you know.
07:40Requires ongoing conversation,
07:41so it's been helpful to get all
07:44these different perspectives.
07:45Uhm, choice of drug.
07:47So what really happens when
07:49you think about the drug?
07:51Well, I'll tell you.
07:53First of all,
07:54you know we went to we went to science right?
07:56And we went to the history that we had.
07:58And as we know in the last decade
08:0015 years there have been a rush of
08:02a series of different no acts that
08:04have been used and proposed that have
08:06different profiles for administration,
08:08safety, efficacy etc.
08:09At the time when we were proposing the trial,
08:13of course apixaban.
08:14Had the what we thought was the safe,
08:18the best safety and efficacy profile,
08:21and the best recommendation from the
08:23American Heart Association for a FIB,
08:24at least at the time,
08:26and so that was a big part of it.
08:28But there was another part of it too,
08:31which was that you know, this,
08:33uh, as we've heard earlier today,
08:35I think from Martin Landsberg,
08:37all of these trials cost a lot of money,
08:39and I think for those of you several
08:42on the call who are proposing trials,
08:44you know we're always trying to cut
08:45those costs as much as possible,
08:47and one of the places where there is a
08:49big ticket is in fact the study drug.
08:51In fact,
08:52you know when the Arcadia trial got funded,
08:55one of the things that really
08:57pushed them over the finish line.
08:58From the 80 to the A1 admission
09:01submissions was the ability to get
09:04the drug from Bristol Myers Squibb.
09:07You know,
09:07essentially at no cost or minimal cost,
09:10you know to to the NINNINDS,
09:12and this comes up all the time.
09:15I'll tell you that we went around to
09:18every manufacturer of know acts at
09:20the time and asked them if they were
09:23interested and you know it was interesting.
09:26I mean, remember these patients
09:27have been excluded from.
09:28Every prior trial of anticoagulation
09:31and not only were they not interested,
09:34several of them told us look you use
09:37our drug and you start to have safety events.
09:40You know you may have lawsuits
09:42on your hand as well,
09:43you know so.
09:45You know there's just a range
09:47of considerations that come up.
09:48I think when you're working with
09:50different manufacturers,
09:50different potential study drugs
09:52and you know we we learned a lot
09:54at those early stages,
09:55so this is sort of what I mean by no
09:59choice of drug and no free lunch.
10:01You know,
10:02a lot of different sort of
10:05background background issues.
10:06What when you end up supplying your
10:08own drug and this was the first
10:11time this had happened in stroke
10:13net where we had a trial that had it for
10:15a prevention trial that where we had to
10:18secure our own our own medication outside
10:21of a sponsor sort of providing it for us.
10:24Well, it raised all these other issues about.
10:26Well, if you're coming up with your own drug,
10:30how are you going to come up
10:32with your own placebo?
10:33And that meant how do you design it?
10:36How do you know how closely should
10:40resemble the actual study drug?
10:42You know when you get the drug from a
10:45sponsor, the sponsor owns the all the
10:48trademarks to the drug so they can really,
10:51truly make they're in a best
10:53position to make a matching placebo.
10:55When you go to a drug that still is not
10:58off patent and you have to make a placebo,
11:01there are issues come up about.
11:05Patents and trademarks actually
11:07so you have to, you know,
11:09somehow thread the needle to be
11:10able to get around those issues,
11:12but also be able to provide
11:14a matching placebo.
11:15So those are.
11:16Those are the kinds of things that
11:17you know we had to work through,
11:18sort of at the beginning.
11:21What about choice of endpoints and
11:23choice of population so you know,
11:25we found this to be really,
11:26really interesting,
11:27and I think something that a lot of
11:29folks here have a lot of interest in.
11:31You know some of the prelim data that we had,
11:35we and other groups have published
11:37really was. First of all, just codifying.
11:39What was I think essentially
11:41accepted sort of clinical question
11:43that it really wasn't sort of
11:46showing efficacy versus you know,
11:49a background.
11:51There's an active comparator arm and
11:53the other piece of that is that you're
11:56trying to figure out the difference
11:59between bleeding and clotting.
12:01And so traditionally, again,
12:04in stroke prevention trials,
12:06hard clinical endpoints like clinical
12:09events have been the main piece of
12:13what's used for trial endpoints.
12:16In a sick population like
12:18brain hemorrhage survivors,
12:20certainly mortality comes into play.
12:22And we saw in our preliminary data
12:25that even when you looked at not
12:29low bar and non low bar patients
12:32that you know certainly these
12:36endpoints were very important,
12:38but so was mortality.
12:39In fact,
12:40you can see that the association
12:42with a protective signal on
12:44mortality was actually quite robust.
12:46Acknowledging that all of these
12:49observation ull charities were
12:51likely highly confounded by
12:53virtue of their their design.
12:55And you can see the point estimates
12:58for ischemic stroke very strong.
13:00Also,
13:00like in prior studies of anticoagulation,
13:04but nevertheless not nearly
13:05as strong as mortality.
13:07The other thing that you can see
13:09that was quite strong was actually
13:12the effect on functional outcome.
13:14And we thought functional outcome
13:16actually might be a really attractive
13:19endpoint for a prevention study,
13:22in part because it may have
13:25more patient relevance.
13:27You know functional outcome and it
13:30is lesion and location naive, right?
13:33We don't worry about whether
13:34or not it's a
13:36small hemorrhage versus a large
13:38recurrent ischemic stroke.
13:39And in some sense, maybe neither
13:41do patients what they care about is
13:43the disability that they're left.
13:45So I'll tell you in our
13:46initial application to the NIH,
13:48we actually proposed functional
13:50outcome MRSI as the primary endpoint
13:53and part of the feedback actually.
13:56Believe it or not from review was that
13:59funk that was thought to be sort of.
14:01Two different 22.
14:02I don't want to say two innovative but two
14:05different compared to prior stroke trials.
14:08So what we ended up doing is
14:10actually making it our key secondary
14:13and then reverting back to a more
14:16traditional stroke endpoint.
14:18I'll finally end in the last couple
14:20of minutes here and and just tell
14:22you as many of you know,
14:23there have been other trials that
14:25have been going on around the world.
14:27Other phase two and phase three type studies.
14:30This was one that was published
14:31just recently in Lancet Neurology,
14:33an open label RCT in the UK.
14:36Lots of similarities, lots of differences.
14:39There was an open label design
14:41they were looking at.
14:43Non inferiority of anticoagulation and
14:45the comparison group had either aspirin.
14:49Or no anti thrombotic.
14:52Ultimately they were underpowered
14:55to look at any efficacy endpoint.
14:59And they had a figure in their
15:01paper that showed the numerical
15:03differences between various endpoints,
15:06and I draw your attention away
15:07from the bleeding and clotting
15:09because we know ultimately,
15:11these were small numbers,
15:12none of which had significance,
15:14but something that we had been
15:15Penguin to a lot of attention to,
15:17and that we continue to do so.
15:18Which was that, you know,
15:19mortality was a part of our primary
15:21endpoint for a number of different reasons,
15:24including the strong effect size combined
15:27with the feasibility of what we needed to.
15:30To propose in order to get a
15:32study funded and to go forward.
15:34But you know,
15:35we're very mindful of the fact that
15:38all causes of death are not the same,
15:40and all of them may or may not
15:43be modified by anticoagulation.
15:45And I think you know this.
15:46This figure may support that.
15:48That's a potential concern going forward,
15:51so that's something that I think that
15:53will all continue to pay attention to.
15:55Those are some of the aspects that went into.
15:58Ultimately, what are our overall aspiring's,
16:02which I think you know,
16:03which is to really look to see if
16:05apixaban is superior or aspirin in
16:07a double blind design on traditional
16:09stroke endpoints.
16:10But we are going to pay a lot of
16:12attention to outcomes like the
16:14modified Rankin and and other outcomes.
16:16The overall design.
16:18I think everyone is familiar with
16:21and you know,
16:22for those of you who are on the call
16:24where we've launched this one campaign.
16:26And in honor of U2 and Bono,
16:29for those of you who are from
16:31that generation, and you know,
16:32we're hoping every center will
16:34be able to just put in one.
16:36So I I think I'm towards the end of my
16:38time. But if there's time for
16:40questions, I'd be happy to
16:41answer any that you might have.
16:44Thank you so much Kevin. I don't
16:48see any questions in the chat box.
16:54I think if anyone has any questions please
16:57type them in the chat box or feel free
17:00to reach out Doctor Chat afterwards.
17:03I think for the interest of time it's 115.
17:06I will move on to the next speaker.