MOST Trial - Opeolu Adeoya
October 27, 2021ID7084
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.