MOST Trial - Opeolu Adeoya

October 27, 2021

ID7084

To CiteDCA Citation Guide

00:00Food I will start with that and I am in.
00:05I'm in Saint Louis,
00:05let me make sure you have the right.
00:07You have the right view on this.
00:11No, no, that's OK.
00:11Do you have the right view on the slides?
00:13Yes, we do. OK, thank you first.
00:15Thank you again to Kevin and the Yale
00:20team for inviting me and giving me
00:23the opportunity to sort of share.
00:25The most war stories,
00:27as I like to think of them and I think
00:29for I feel like it's a set up speaking
00:32after Kevin and month 'cause they they
00:35covered everything I always have to say.
00:38But I will.
00:39I will give the most perspective
00:41as much as I can come here,
00:43my disclosures.
00:47And so most as everybody on
00:49the call knows is the multi
00:51optimization or stroke thrombolysis.
00:53I'll fly through the first like
00:5510 slides or so and then get into
00:58more of the narrative than Humana.
01:00Kevin, we're just providing.
01:02This is a sort of a trimmed
01:05down theme and structure,
01:08similar thing in terms of same science.
01:13Statisticians the data management
01:15and using the infrastructure of
01:18stroke Nets to do the enrollment.
01:21And I like humans comments about not being.
01:24I can't remember how you phrased it,
01:25but something about you're
01:27not actually in charge of it,
01:29and so a lot of what we do.
01:32I heard somebody say recently
01:35that organizations are like like.
01:38Sort of conversations right,
01:40and so I think clinical trials
01:43are conversations, right?
01:44And you as the as the designated P or
01:48the designated lead in some fashion.
01:51You can facilitate and Foster
01:54and drive and shape and tilt.
01:57Ultimately these are conversations,
01:58and if you if you can't convince people
02:01you're not going to make progress.
02:04Sent to the larger team, uh, using what?
02:07Again,
02:07the narrative of what woman was
02:10proposed in a few minutes ago.
02:12This is loosely what we put in the
02:15grants and dumb this portion over.
02:18Here I will talk about as it relates to
02:20the pharmacy and the drug distribution
02:23and what ultimately happened with that.
02:28The overall study design,
02:30you know it's an adaptive
02:32randomization design.
02:33We're studying two interventions
02:35Argatroban on the one hand and
02:38after febrile tide on the other.
02:41And we're combining either of
02:43those medications with standard
02:44of care thrombolysis.
02:46So who made comments about how the trial
02:49moves and how things constantly change?
02:51We initially proposed this as a CPA trial.
02:55We subsequently with some navigation and some
02:59data and some conversations with the FDA.
03:04We got two allowed to negative place as a
03:07standard of Catherine Bellis as practice
03:10shifted over the life of the trial.
03:13Uhm,
03:13like the aims.
03:15Uh,
03:16efficacy of the drug of the drugs
03:18and the safety of the drugs,
03:20with Maine eligibility being
03:22patients who are treated within
03:25three hours of symptom onset with
03:28moderate to severe ischemic stroke
03:31and vascular therapy is allowed,
03:34and this is this is part of the sort
03:36of evolution of the life of the trial.
03:39Will talk about that in a second.
03:41The primary endpoints.
03:42I think everyone is.
03:43Aware of which is a 90 day right
03:46ranking as well as a SICH rates.
03:50So it's hard to imagine now.
03:53But in October 2014 and it was
03:56interesting to see who minds only
03:5814 dates and Kevin's aspire concept
04:01and how long all these things
04:03take to sort of come to fruition.
04:05And so we actually submitted.
04:07So we must have,
04:09we must have submitted that concept.
04:12But a year before reminded of Arcadia.
04:16But we we actually submitted
04:19the grant October 2014.
04:21And again, it's hard to imagine now.
04:23But in March.
04:2413 is when I miss 3 synthesis
04:27and Mirsky were published in the same
04:30issue of the New England Journal and at
04:34that point everybody at least there was
04:37concerned that thrombectomy was dead and
04:40we're never going to be able to prove
04:42the the efficacy of this intervention.
04:46So as we were preparing most submission
04:49we knew these trials are going on
04:52and we're like oh, what do we do?
04:54How do we? What do we say or don't
04:56we say about about thrombectomy?
04:58And how do we include or not include it?
05:00Well, we use what we considered
05:02was best evidence at the time.
05:04Which were these three trials?
05:05And we said we're just going to do Ivy only,
05:10and if and if practice changes,
05:14we'll see how practice changes,
05:15but we didn't have much to go on, right?
05:17And so of course. October 29.
05:21It's a clean.
05:22It was presented in Turkey at the
05:24at the World Stroke Organization.
05:27Meeting was where Mr Clean was
05:29presented in Turkey on October 29,
05:31with us having submitted October 5.
05:35So we scrambled. We do all sorts.
05:37We try to save the application,
05:39but ultimately this is a summary
05:41statement was that there's a dearth of
05:43safety data and we had this sort of,
05:45you know.
05:47Multi arm multi stage components
05:50of the design that would have
05:53allowed us to sort of actually look
05:55at safety in the thrombectomy.
05:58Patients and see whether or not a
06:01particular intervention was causing
06:02trouble with with ectomy patients,
06:04and so on.
06:06We see Kevin's point about the
06:09open label design.
06:10We initially proposed this open label
06:13design and there was a lot of concern.
06:16Especially as a medical intervention
06:20about making sure we double blinded,
06:23we were concerned about the feasibility of.
06:27Successfully double blind in,
06:29but we figured it out.
06:31We put this all together and create
06:34work with a good manufacturing
06:37practice facility and put together
06:40this double blind design.
06:42Even as we did that,
06:43even as we went through this process,
06:46we had enchanted get published in 2016.
06:50We had no test get published in 2017,
06:54and as human was was talking again,
06:57we're using standard of care,
06:58thrombolysis with .9 mix, Poughkeepsie CPA.
07:02That's what our data was based on.
07:04That's what I safety was based on that.
07:06So that preliminary efficacy
07:08estimates are based on.
07:10So as we're doing that, there's just.
07:12All these potentially like you know,
07:15epic shifts in the field during
07:18the life of the proposal and
07:20the and the and the concept.
07:22And ultimately neither these
07:25changed change clinical practice.
07:28Or you can imagine that and.
07:31A program and was phenomenal in terms of.
07:36Collaborating and informing us as the
07:38trial went on and being very helpful
07:40as we as we even before the results
07:43were fully released and sort of guiding
07:46us and and how best to approach this.
07:49And then I say Eureka Ish 'cause
07:52this is the notice of award in
07:55September 2017 as everybody sees that.
07:58So we're like yes we did.
07:59It only took you know from concepts to
08:02notice of award about four years 4 1/2 years.
08:06So we're all excited.
08:07And then this happened, right?
08:09So I don't know if everybody remembers this,
08:11but in the in late in the fall,
08:15early winter of 27 is when the
08:18government shutdown and so we
08:20then had all that so navigates.
08:22Do we? Or do we not?
08:23Are we able or we're not able?
08:25Now we got into the logistical even
08:27after we then got the funding issued.
08:31The startup process,
08:32which is something that I I don't
08:34think Kevin and woman talked about,
08:36but from that 2017 through
08:42our first patients,
08:43in was actually about two years for us and
08:47I will talk about that in a second so far.
08:52Here's where we are and somewhere over
08:55here in 2020 was the pause due to COVID,
08:59which we haven't talked about.
09:01Now you can see how our trajectory was
09:04going up prior to COVID relative to
09:08our projections and then with COVID
09:10and then since COVID we just haven't
09:13quite gotten back on that line in
09:16terms of enrollment and a lot of that
09:19is staff turnover for the hypercube trial.
09:22It's just a lot of
09:24resources on that front end,
09:26as you know and you do this well
09:28and so trying to get us to get back.
09:31Amtrak has been a little bit of a challenge,
09:33and So what are those challenges?
09:36You know,
09:37we we got the feedback from reviewers.
09:40That said, we had to double blind,
09:41so we created this process.
09:43We were excited about the process.
09:45We work with the GNP facility.
09:47And then this is the first that I got into
09:51supply chain issues and we still have,
09:54I believe,
09:54a glassware supply chain issue
09:56in the world and the amount of
09:59time and energy that iris,
10:00the project lead and I spent on trying
10:03to figure out where we get glassware and
10:07how to get glassware and how we order it.
10:10And whatever we became experts
10:12in the supply chain of glassware
10:15for manufacturing and.
10:17Ultimately,
10:18when when they when they delivered?
10:22The very first, uh, set of, UM?
10:27Prepared study drug by the GNP facility.
10:30I don't have the picture.
10:31Actually kept the picture or somewhere
10:33where there's like little black flecks
10:36inside our study drug right and for
10:38some of the bottles you shook them
10:42and there were little floaties like
10:45visible floaties to the eye in the
10:48study drug when it was delivered
10:49and so we had to cancel all that.
10:52Went back to the NINDS.
10:54Janice is been.
10:56A sharper extraordinaire
10:58through this whole thing,
11:00so I'm back to Scott and Claudia
11:02back then and try to say OK,
11:05how do we fix this with what
11:07we already a good?
11:08I think at this point a year and
11:10a half from study startup we
11:12extended year one of the award so
11:14as opposed to whatever the dollar
11:16amount was that we got for
11:19the first year as opposed to
11:21sort of just burning through
11:22that we slowed the burn rate.
11:24And again these are conversations.
11:27So we talked to that NCC when we
11:30talked to the NDMC and we talked to,
11:33you know, image in core and we talk.
11:37You know we can't.
11:38We can't not support the coordinators.
11:40There's a limit on how much
11:42of our investigator salary.
11:44Then I it should allow us
11:46to change without approval.
11:47So we discussed all.
11:49We've talked again with all those
11:52groups and were able to have year
11:54one actually be September 2017.
11:57I think I forget about the dates.
11:59I think the notice was in September.
12:01The dates actually began in March in May.
12:04I'm sorry so year one then went
12:06through 2019 of the award effectively,
12:09so we extended it right immediately.
12:12We extended the life of the trial
12:14and the front end because of all
12:17the manufacturing issues we had.
12:19Uhm,
12:19the side activation delays remain
12:23an issue for us actually because
12:25we we proposed 110 sites and man
12:28showed their Arkadiusz progression
12:31to the optimal number of sites.
12:34We're still only at 63 and a lot of
12:37that from a hyper acute perspective,
12:39being the fact that a lot of
12:42sites can't do that sort of,
12:45I don't think we need 24/7 in most.
12:48I think we need sort of five to
12:5110:00 PM for when those Trimble
12:54access patients come in,
12:56and so once we sort of start talking
12:58to sites and where and they say we can
13:00only do it from 9 to 5 essentially
13:02and we're asking for 5:00 to 10:00 PM.
13:05It gets a little challenging
13:06because we just don't have in.
13:08We just don't have the workforce as it
13:10exists right now to be able to support that.
13:13Uhm,
13:13it's an active place.
13:14I included two already and so we use
13:17this meta analysis by Jeff and I had
13:20a conversation with the FDA about
13:23whether or not we can incorporate that.
13:26The case we made.
13:28And as a trial,
13:29we cannot dictate standard of care,
13:31right?
13:32And so the case we made was a
13:34standard of care with shift in
13:36and we reference published papers
13:38and we reference clinical practice
13:40and we referenced,
13:41I think the A guidelines actually was a
13:44level two recommendation for TENECTEPLASE,
13:48and so we reference all these things
13:51referenced method analysis by Jeff and
13:53and sort of at the end of the day,
13:55crossed our fingers and sent something
13:57to the FDA with the protocol amendment.
13:59Come and come,
14:00and it was actually a lot easier than
14:03that we anticipated fortunately,
14:06and so that got incorporated into the trial.
14:09We got stopped tonight just for
14:11COVID well we got stopped lasts
14:13about a year ago now I think I was.
14:16A little less than a little less
14:18than a year ago we got stopped
14:21in December by the IRB.
14:23From December through,
14:24I want to say we did the training
14:27in January and we probably restart
14:29it back up
14:30in February, but then it's taken a lot
14:33to get the sites back up to speed and
14:36the reason we got stopped was because
14:39we are having these dosing errors.
14:41Uhm, we actually started the trial
14:44even though I talked about the GMP
14:47GMP facility issues, we started
14:49the trial with a double blind drug.
14:52And, uh, you know, back then,
14:55when everything was double blind
14:57and we had maximum volumes and we
15:00weren't going to have dose and errors
15:02there were there was an instance of
15:04somebody running from a investigational
15:06pharmacy with the study drug.
15:08And there's there running the
15:10drug flew out of the vile,
15:12flew out of their hands,
15:14landed and shattered everywhere, right?
15:17And so at the beginning of the
15:19trial we had issues with just
15:20sort of all the time pressures.
15:22And that was one of those stories that
15:24you can't really make up that happened
15:26as they're trying to deliver study drug
15:28vial flew out of the hands and shattered,
15:30and so with the dose and
15:32administration errors.
15:33As you know,
15:34we've talked and hopped on the
15:36randomization verification form
15:37and those COVID workforce issues.
15:40We've already talked about,
15:41and this group knows this.
15:43You do this well,
15:44but I just have to put the randomization
15:46verification form off there so that
15:48everybody is looking at that to
15:50inform our dose in as it relates to.
15:53Actually,
15:53given the other actors,
15:55so prints it's take a picture of it
15:58and make sure that we have that handy.
16:00The effort cues that have come
16:02up during the course of the life
16:04of the trial is sort of deciding
16:07whether to randomize or not.
16:09Trying to figure out whether we can
16:11get the study drug to the bedside
16:13on time we can get study drug within
16:1520 million time of about 24 minutes.
16:17While we have lots of outliers and
16:20can't remember what the number was,
16:22I was just looking at this yesterday.
16:24But overall,
16:24the number of people that go beyond
16:27our 75 minutes is relatively low
16:30and we have 250 subjects and.
16:32Roll today,
16:33I think Temple just enrolled
16:35it's 11:50 at subject today,
16:36so we're making progress.
16:38It's very exciting where over
16:3920% of a maximum enrollments,
16:42and anticipating that we probably
16:44won't get to the national numbers.
16:47So how much time do we have?
16:49We struggled as a central study
16:51team about allowing people to
16:54go beyond the 75 minutes.
16:55It wasn't a safety issue.
16:58But we because it was a protocol
17:00issue or would probably well over
17:02prioritizing the notion of the
17:04protocol violation well after
17:06the first handful of subjects,
17:08it became pretty clear that we're
17:10going to just accumulate a bunch
17:12of control on subjects and not be
17:14able to show a difference unless
17:16we actually gave a study drug.
17:18And so we engage in conversations
17:20with the team and make sure they
17:23don't have any safety concerns.
17:25In general,
17:25we still want everybody to sort
17:27of give
17:28the drug. Quickly as possible because we
17:31think that overlap is effective, we want.
17:34Please possible discontinue we now
17:37I single blind design and so if we
17:40don't stop pasivo we have we run the
17:43risk of sort of compromise in that
17:45single blind design and so if there's
17:48anything related to placebo and it's
17:50sort of neurodegeneration or bleeding
17:52complications with stuff that also,
17:55the PCC is something that you
17:57know if if there's no.
17:59Reason why we expect the patients have a
18:02normal PC would just say call the hotline.
18:05The fact that we have Turkey three
18:07and we haven't quite given drug yet.
18:09This is a question that comes
18:11up from my perspective.
18:13We still think that sort of microthrombi
18:16that contributes to overall
18:19functional outcome in the long run,
18:23and so we would sell advocate
18:25given the most study drug.
18:26And you know,
18:28oftentimes the the the interventionists UM
18:3263 that 62 a when read by the central reader,
18:37and so our perceived 63 when
18:38we're the ones that do,
18:40the procedure isn't always real,
18:42so just caution against that.
18:43Also we've had some issues with
18:46the website being down and so I
18:48would just call the hotline and we
18:50can help can help facilitate that.
18:54This is where we are.
18:55This is the figure from yesterday to
18:57fit 249 yesterday or at 2:50 today,
19:00and ultimately I want to wait to
19:01be like yo you can see all these
19:03people down here if all these people
19:05were like Yale would do so much
19:07better than we're currently doing.
19:09And so I just want to sort of
19:11ingratiate myself and thank you
19:13all for the efforts that that yell
19:15is putting into most and thanks
19:17again for the opportunity.
19:18I'll stop there and stop sharing.
19:21Thank you so much.
19:23I personally have learned so much from UM
19:27from this and you sharing your experience.
19:30I'm sure everyone on the call
19:32feels the same way and I'm sure
19:35everyone shares the same sentiment
19:37that Kevin put in the chat box.
19:39Persistence while so thank
19:41you so much for this,
19:43and I think we're at 2:30 now,
19:46so we'll move on to the.