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INFORMATION FOR

ASPIRE Trial - Kevin Sheth

October 27, 2021
  • 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.