Joseph Broderick - Harnessing the Power of Clinical Trial Networks for Stroke - NIH StrokeNet

October 27, 2021

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00:00This brings us our next talk,
00:02which will be given by Doctor Rodrick.
00:05I'll hand it over to doctor Karen
00:07Fury from Brown University.
00:09All introduce Dr.
00:11Broderick and she will moderate
00:13this session as well. Great thanks.
00:15Shawty uhm we are very fortunate
00:18to have Joe Broderick with us today
00:21to deliver a keynote address.
00:23Uhm, Joe is currently professor and
00:26director of the University of Cincinnati,
00:30Gardner Neuroscience Institute.
00:32He's been at the University of
00:35Cincinnati since 1987 and was
00:37chair there from 1987 to 2013.
00:40He's been a leader in stroke net
00:43since its inception in 2013 and
00:46is currently the director of the
00:49Clinical Coordinating Center.
00:51Joe is truly a giant.
00:53In the field of stroke,
00:54as all of you know,
00:56he has been either the the P or on
00:59the investigative team of all of the
01:01major trials that have moved forward.
01:04Acute stroke therapies including
01:06TPA and into vascular therapy.
01:08He's been interested in intracerebral
01:11hemorrhage and has really
01:13transformed the field from one of
01:15passive diagnosis of stroke and
01:18intracerebral hemorrhage to a field
01:20where we can actively treat people.
01:23And improve outcomes.
01:24He's also been mentor to many of
01:27today's leaders in stroke and received
01:30awards from the American Heart Association,
01:33including the Clinical Research Prize,
01:36the Feinberg Prize and the
01:39Visionary Research Award.
01:41So it is truly a pleasure to have Joe here.
01:44He's in the unique position of,
01:46you know,
01:47having been part of the evolution of
01:50stroke clinical trials for several decades,
01:53and today.
01:53He's going to share his vision for
01:55the future. I'll hand it over to Joe.
01:57Thank you.
01:58Thanks so much, Karen,
01:59and it's a pleasure to be here.
02:01This is a great conference.
02:02What a great organization.
02:04It's like seeing the best
02:05tips from stroke debt here,
02:07so it's it's been wonderful and I
02:09really appreciate the opportunity
02:11to talk today about harnessing the
02:14power of clinical trial networks
02:16for stroke in the United Stroke net.
02:19So I'm going to.
02:20This is my disclosures.
02:25And there's a lot of advantages of national
02:28clinical trial networks and stroke Ness,
02:30not the only one in the world.
02:32There's a number of other ones
02:34they'll talk about towards the end.
02:36One of the advantages of a network is
02:38that you can combine the mini minds
02:40and ideas across the network to divide
02:43the best important clinical questions
02:45and design trials to address them.
02:47And as I show you,
02:48I think we got a pretty good pipeline, we.
02:50Boy, it's one of the pleasures of
02:52my job as they give works with
02:54so many smart people from so many
02:56places who really had great ideas.
02:59I think one of the biggest reasons
03:00for at trial network so you don't
03:02have to build a new infrastructure
03:04across the country or globally.
03:06Every time you set out to do a new trial,
03:09the infrastructure is always ready to go.
03:12At those sites that are
03:14successful recruiters,
03:15you could have a centralized Institutional
03:18Review Board consistent contract ING.
03:20You can share best practices across
03:22the trials of network which we do.
03:24You can have an experienced central
03:26research pharmacy which helps when
03:27you're preparing a trial for submission,
03:29but also with getting the trial done.
03:31And finally,
03:32finally,
03:33it's a partnership with our government
03:35research funding agencies in Inds
03:37in this instance,
03:38but other countries have funding
03:39agencies well,
03:40which are pivotal for the access
03:42of these networks.
03:46What's our vision? Our vision is
03:47to be a leading platform for stroke
03:49trials in the US and globally.
03:54Just a quick review of the
03:57history we started in 2013.
03:59Actually, the national Data
04:01Management Center was funded in
04:032014 and the regional center soon
04:05after we have 27 regional centers.
04:0824 that are currently funded with
04:10over 500 satellite hospitals.
04:12The National Coordinating Center at
04:14the University of Cincinnati and the
04:16National Data Management Center at the
04:18University Medical University of South
04:20Carolina and this network with the
04:23regional centers is designed to do.
04:25Phase two and phase three stroke trials,
04:28as well as ancillary trials and
04:30biomarker studies that focus
04:31on acute stroke treatment,
04:33prevention and recovery.
04:37This is actually from earlier in
04:38the network fully, I think before
04:40even the second phase of funding,
04:43but it shows that even at that
04:46time 60% of the US population was
04:48in a 65 mile radius from a stroke
04:50that site and I would say now it's
04:53probably higher in the range.
04:54My guess would be in the range of 70%.
04:58This is our organizational infrastructure
05:00and we have the two coordinating
05:02centers and National Institute
05:04neurologic disease and stroke.
05:07And then we have a steering
05:08committee which is represented by the
05:11regional coordinator leaderships,
05:12such as here with Spirit Executive
05:14Committee which has membership
05:16of the coordinating centers,
05:17NIH and also representation from the RCC
05:22and then the Operation Committee which
05:24meets weekly that examines and looks
05:26at all the ongoing trials which also.
05:28Had their own separate Operation committees,
05:31executive committees, etc.
05:33We have two cores imaging core with a
05:35lot of what we do in stroke involves
05:38imaging and then it educational
05:39core which has been extraordinary,
05:42active and successful since its and really
05:44came out of the original educational
05:46cores that were part of spoke Prius,
05:49which is the network which
05:50preceded and I had stroke net.
05:52The working groups which are really
05:55instrumental in looking at the ideas
05:57for the trials and helping work with
05:59the P eyes to get them in great shape
06:02to submit and then also eventually
06:04helping assist with trials as they get
06:06going when there's an issue that comes up.
06:09The advisory committees
06:10are also very important,
06:11such as the Minority Recruitment committee.
06:14Also, there's the end of vascular committees.
06:16There's different committees there that
06:18as we need questions to be addressed,
06:20we can turn to.
06:24But I'm going to show you this,
06:25which gives you an idea of our pipeline.
06:27So this is of July 2021.
06:30And believe it or not,
06:32since beginning we've had 122
06:35trial concepts have been reviewed.
06:37That really is quite a pipeline.
06:3946 acute, 46 prevention,
06:42and 30 recovery Now what happens
06:44is those trial ideas go to Indians
06:47to a committee that says is this
06:49consistent with our mission?
06:51Maybe it should be better someplace else,
06:53or we already funding something
06:54similar to that.
06:55But after that is gone through
06:58there was 46 that were approved to
07:01go forward for the full evaluation
07:04of feasibility and at one time
07:06though six of these were tabled
07:08and I'll talk about them.
07:09Platform concept in just a little bit, but.
07:13The bottom line is at the 42
07:16applications that were submitted,
07:1932 were resubmitted because they needed
07:21to make some changes based upon the review,
07:24but of those 15 so far have
07:26been funded or approved,
07:27which is 36% of those reviewed,
07:30which is quite a high percent
07:31when you look at large grants
07:33submitted for funding to the NIH,
07:35and I think it reflects the
07:37careful work of the working groups
07:40and of the whole network working
07:42to provide the best possible.
07:44Trial ideas and concepts for
07:46consideration of funding.
07:50So this gives you an idea of how quickly
07:53the number of trials has increased.
07:56We had a few back in 2015,
07:59but we're now up to 17 trials that
08:01are currently ongoing in the network,
08:04and that doesn't include some of the
08:07trials that have been completed.
08:09So this is the ongoing stroke net
08:11clinical trials we see up here.
08:12The completed trials.
08:13We see how the ongoing and just to
08:16Orient you the black trials are trials
08:19that were funded independent of stroke
08:21net and the words they went through
08:24a different mechanism for funding.
08:26But stroke net was a great
08:28participant and actually tell rehab
08:30was done all within struggled net,
08:32but the red ones are trials
08:35that came from idea and working
08:37through the initial concept.
08:39All the way to funding and then
08:43either completion or than ongoing
08:45at currently and then the blue one
08:48is a trial that we'll talk about at
08:50the end that's approved by Council,
08:52but it's yet to receive funding,
08:53which hopefully will occur.
08:55Probably the beginning of 2022.
08:59So what have been the outcomes
09:01and impact of stroke trials?
09:03Well, I think all of you are
09:05very familiar with diffuse three
09:06and the spirit sites played an
09:08important role with that trial.
09:10It was stopped early.
09:11It was a highly positive trial
09:13published in New England Journal
09:15Medicine and along with the dawn
09:17trial which is going on at the same
09:19time it led to immediate change
09:21in clinical practice and stroke
09:23guidelines with lives changed worldwide
09:25throughout the world and in 2018 I
09:29received the distinguished clinical.
09:30Research Achievement Award and I
09:32know the P eyes of the of the diffuse
09:35three were barely proud of it,
09:36as as was our whole network,
09:38but that's the top on the top three of
09:40all clinical stroke trials and US in 2018.
09:44Second completed trial was
09:46the teller rehab trial,
09:47which was the first randomized trial of
09:50liability patient for stroke patients
09:52was published in JAMA Neurology.
09:54The trial demonstrated that Tiller
09:56rehab is not inferior to in clinic
09:59therapy for improving our motor status
10:01in patients who've had a recent stroke.
10:04And with our experience with COVID,
10:06it shows the future importance of
10:09this technique is particularly
10:10with those in general,
10:11have limited ability to travel,
10:13and there is two comments by PM Duncan
10:17and Julie Bernhardt and stroke of 2021,
10:20which said with the widespread
10:23adoption of telerehabilitation
10:24catalyzed by the COVID-19 pandemic,
10:27this approach provides great potential
10:29for improved care equity by addressing
10:32the geographic you live far away from the.
10:35Comprehensive site,
10:36demographic and social economic barriers.
10:43So. We all know about COVID.
10:46It's impacted every one of our lives in
10:49the conference here packed it personally.
10:52Professionally,
10:52with the health of their patients,
10:55but it's had a tremendous impact on
10:58clinical research and to Orient you to
11:01this slide are are cute trouser on the
11:03top that's most are prevention trials
11:05or in the middle and the bars and
11:08each one of these bars represents the
11:10number of recruitments per month and
11:13our recovery trials around the bottom.
11:16And based upon what happened with COVID,
11:18we made the decision to shut
11:21down the network for safety.
11:23Of the patients that we're trying to enroll,
11:25but also the safety of our research
11:27staff and we would then just from
11:30about six day weeks completely
11:32reconfigured the protocols of the trials,
11:35how we were going to access patients,
11:37how we were going to liver drug.
11:39And how even did consent virtually
11:42by E consent.
11:44And we did that within a couple
11:46months time such within 55 days we
11:49had restarted the trials of a few
11:52days later for the therapy trials,
11:54but I think it shows how quickly
11:57we could respond as network to a
11:59really a crisis and how we could
12:01redesign what we were doing to come
12:04up with a better approach,
12:05not just maybe for in this time of COVID,
12:08but also trials in the future.
12:10And you can see that we got back
12:12up to recruitment pretty well,
12:13although I would say that we're still
12:15not quite at the rate that we were for
12:18some of the trials prior to kovit,
12:20and we're still in the midst of the pandemic,
12:22as we well know.
12:24So here are the trials,
12:27but the completed trials already
12:29talked about Diffuse 3.
12:30But the ongoing trials have just
12:33just a broad range of clinical
12:35questions we're trying to answer.
12:37So Crest two in Crest age.
12:40We're looking at gradually rasterization
12:43for asymptomatic chronic stenosis,
12:45either by stenting or by endarterectomy,
12:48and comparing that to best medical therapy.
12:51Arcadia we're looking at cryptogenic
12:53strokes and we're looking at patients
12:56who have one of three cardiac
12:58markers and then seeing whether
13:00apixaban or aspirin is a better way
13:02to prevent strokes and outcomes in
13:05these patients are KSI is looking
13:07at cognition in silent infarcts.
13:10In their KD patients.
13:11Save Smart is looking at a broad
13:13range of the scheming stroke patients
13:16and saying if we can identify
13:18sleep apnea in the hospital,
13:20does treatment using CPAP equivalent
13:23improve outcome and also prevent
13:26strokes better than just standard care?
13:29Most is a trial that's trying to see
13:32whether we can add something to TPA
13:34given within three hours of onset and
13:37improve re perfusion and outcomes.
13:39The two agents are eptifibatide
13:41which is affect platelet function in
13:44Argatroban which is an anti thrombin
13:46molecule and patience in this truck
13:48can also can endovascular therapy.
13:50In fact 40% of patients have transport
13:53two and I acquire our two covered trials.
13:57Transport.
13:58Two is looking at.
14:00Upper extremity motor recovery
14:01in patients who've had a stroke
14:04and we are comparing transcranial
14:07direct stimulation plus modified
14:09constraint to sham transcranial direct
14:12stimulation plus modified constraint.
14:15I acquire is a very exciting
14:17trial for little babies.
14:18You know, infants 818 months to
14:21three years who had a stroke due
14:23to an arterial blockage at some
14:25point prior to that and then using
14:28a very intensive rehabilitation of
14:30six hours a day or different time.
14:33Actually different amounts of rehabilitation,
14:36and it's very specifically designed for kids.
14:39It's like playing with them very
14:41intensely or going through their
14:42activities of daily living,
14:43but doing it for six hours.
14:45In a very concentrated way for four weeks,
14:47and that's compared against standard therapy.
14:50And then we follow up patients out
14:52to six months and the control group
14:54can actually then elect to go and get
14:57the intensive therapy after that.
14:58So it's a very satisfying trial for
15:01parents with kids with young kids
15:03with stroke about having something
15:05that can maybe help their their young
15:08young children aspire and Saturn aura
15:11two prevention trials for ICH and.
15:15Kevin Shaft here at at at Yale,
15:17is the contact P for Aspire and here
15:20we're looking at patients who've
15:22had predominantly deep hemorrhage is
15:25also have atrial fibrillation and
15:27the decision is should we be using
15:30at a pixel BAM or aspirin to prevent
15:33bad vascular outcomes in the balance
15:36between hemorrhage and also the
15:39ischemic events.
15:40Saturn led by Maggie Celine,
15:43is looking at patients who have
15:46global RICH S.
15:47And then also have been on a statin
15:49agent in time with their hemorrhage.
15:51And here we are deciding whether
15:53to keep him on or take them off.
15:55Which is better? It's a very pragmatic trial.
15:59Activating Achensee or two COVID
16:01platform trials that involves
16:03stroke net include stroke patients
16:05but also include a number of other
16:08networks across the country.
16:10Fastest is the newest acute stroke
16:11treatment and this is a trial focused
16:14on patients with intra cerebral
16:16hemorrhage and the treatment.
16:17Here's we commented factor 7A
16:20versus pussybow,
16:21but it has to be given within
16:22two hours of onset,
16:23so one of the ways that we're doing that
16:26is focusing on exception from informed
16:28consent and also mobile stroke units.
16:30And this is one of our global trials.
16:32It's it's also taking place in Japan,
16:35Canada and Europe.
16:37And we're going to talk in more
16:39detail about Captiva verifying
16:41rapsodie to in just a moment.
16:46So what is in the future?
16:48What is in potentially in your
16:50future if you're going to be at
16:52one of the sites for these trials?
16:53So let's talk first about Captiva.
16:56Certainly they have the best
16:59looking location for a trial.
17:00If we could all do it there
17:02and do it all year round,
17:04but the piece for the trial,
17:06Brian, who is is the first
17:09nurse surgical P as a primary P
17:12contact P for the trial Mark Cho.
17:14It's also act as a P at the
17:17medical versus South Carolina.
17:18Sherry Yates is the statistical P
17:21Renee is also another statistical
17:24investigator and then Tonya
17:26Larissa play important roles.
17:27The study as well and again this is a
17:31trial that has funding from the NIS,
17:34but also has participation from
17:36the industry and that Jackson
17:38provides river rocks.
17:40Abandoned funding for Pussybow and Astra
17:42Zeneca is providing Thai capital or.
17:47So this is a three arm trial.
17:49Were trying to answer what's the best
17:51way to prevent an ischemic stroke,
17:54at least medical prevention with somebody
17:56who has a high Gray into the cranial artery.
18:00Stenosis associated with an ischemic stroke,
18:02so we're gonna need a lot of
18:05patients to address that.
18:0616183 subjects with a symptomatic
18:08infarct due to 70 to 99% of the
18:12symptomatic inner cranial stenosis.
18:14They have to have a non disabling
18:16symptomatic infarct within.
18:1730 days and it has to be one of these
18:20arteries defined by these imaging techniques.
18:23It's randomized in a one to one
18:25to one and it's double blind.
18:27And the three arms are tight.
18:29Aguilar plus aspirin versus rivaroxaban
18:32at a low dose versus aspirin
18:35and clopidogrel versus aspirin,
18:37which is really kind of considered the
18:39standard of care right now for three months.
18:41Although in this trial it goes out
18:43all the arms go out to 12 months.
18:45We also sampled for genotype,
18:47which has to do with how literal
18:50is metabolised and becomes active,
18:52and this can vary with patients.
18:55And then we do intensive risk
18:57factor management.
18:58For all of that,
18:59all the arms just like insane person.
19:01Press two and then the follow
19:02up goes out to 12 months.
19:06So why do a three arm study?
19:08Well, it's timely and we have some
19:10new information that's exciting
19:12about ways that maybe we can improve
19:14upon what we're already doing.
19:16So, for example, we have great
19:18data for capital and aspirin,
19:20at least for the first several months.
19:22For point enchants,
19:23we have data for Chi, Cago,
19:26and aspirin from the sales
19:27and the print studies,
19:29and we have data from about low dose
19:31river rocks abandoned aspirin for
19:33the compass and Commander HF trials,
19:36and it's efficient 'cause
19:37we have one control arm.
19:39And the comparison is to the
19:41completed role plus aspirin arm,
19:43which is the control arm not
19:45against the respective arms.
19:46So we could come up with two
19:48effective treatments and that
19:49would be nice to have and we
19:50have to decide which one to use,
19:52but that would be a good problem to have.
19:56Let's talk about Ty Cobb Award for those
19:58who might not be as familiar with it.
20:00It's a direct P2Y12 receptor antagonist.
20:03It has maximal platelet reactivity
20:06inhibition at one hour versus critical,
20:09which is much longer.
20:11It does not require the activation or the
20:15metabolism of the critical like it does,
20:18like it is for compatible.
20:20And tackle is actually more
20:22effective than compatible,
20:23irrespective of the of the
20:25carrier status or the genetics.
20:27And that's true with a number of
20:28different trials in cardiac trials.
20:32Just want to point out the
20:34the the area of interest.
20:36The population interest for us is
20:39this inter cranial artery disease
20:41and this is from fails and if we
20:43look at patients treated with Taika
20:45galore versus placebo we see that
20:48there is a strong protection of
20:51prevention of stroke and the trike
20:53Agler group in this particularly in
20:56this group and also the event rate
20:58is higher in this group than it is.
21:00Overall, we know that this group is.
21:03Particularly high risk group,
21:04as we found in samples.
21:10This is data from the compass trial,
21:12which was more of a generalized trial.
21:13How we take care of patients
21:15with atherosclerotic disease
21:17and preventing ischemic events,
21:19and you see that for stroke,
21:21it actually was effective.
21:23Highly significant difference.
21:24The reason why this is such a low rate
21:26is because a lot of these patients
21:28didn't have a stroke to start with,
21:30but the Nice comforting thing is that
21:32the hemorrhage intercell heavy drag
21:34was similar between the two groups,
21:36although there was more bleeding
21:38in other places.
21:42So what, uh? Why are we doing your 12 month?
21:46Treatment rather than three months.
21:48Well, the rates of recurrent
21:50stroke in the territory.
21:51That's not a garden where the
21:53double from 3 to 12 months in
21:55samples and half of US stroke.
21:56Neurologists surveyed always use capital
21:59in asper for longer than three months.
22:02But this is even I think,
22:03more interesting.
22:04You may not know that in Sampras
22:06there were fifty medical armed
22:08subjects who took Lipidic own
22:09aspirin longer than three months
22:11because of cardiac clearance.
22:13Maybe they had a recent standards
22:14that with the last couple of years,
22:16but you see that those people that
22:18had the treatment for more than
22:20three months had A at a decreased
22:23primary endpoint compared to
22:24the ones who got the traditional
22:27treatment within three months.
22:29And there was a little bit increase,
22:31but not significant difference
22:32in major hemorrhage.
22:36So what's captivus timeline?
22:37It's planned for five years.
22:39We're going to six months startup,
22:4138 months of woman,
22:4212 months to follow last,
22:44patient out, and then data analysis.
22:46We hope to get 4.6 subjects
22:49per site per year.
22:51We're going to need 115 sites.
22:53Site selections essentially done,
22:54and we hope to be starting here in 2022.
22:58Investigating will probably be
23:00in the first several months,
23:022020 for sure.
23:06So let's talk about the other next new study,
23:09which is verify I happen to
23:12really also like there there.
23:15Dear Monica, for the study and it's
23:17a validation of early prognostic
23:20data for recovery outcomes after
23:22stroke for our future higher yield
23:25trials and the title does say at
23:27all in terms of what they're trying
23:29to come here trying to accomplish.
23:31So you can see here the pies on the left,
23:33pushing country as a contact P.
23:35Steve Cramer, Cathy Stanier,
23:37Telegol and then key other people on the
23:40other side in terms of project managers
23:42and statistics and data management.
23:47So what are the deliverables I'm
23:49going to start with the deliverables
23:51and will go into the details.
23:52What they want to do is to have a
23:55reliable way to predict patient
23:57outcomes soon after ischemic stroke,
23:59such that we could stratify patients
24:02into the right type of therapy approach
24:05and also design trials much better,
24:08because if you're going to take a
24:10person who's not going to respond
24:11with physical therapy or whatever,
24:13why would you want to put them
24:15in trial testing that?
24:16But if you have somebody who know,
24:18tends to get better,
24:20then can we improve upon that, can we?
24:22And when should we intervene?
24:24But stratification will be helpful.
24:26It's sort of like the difference
24:28when the acute stroke trials where
24:29we know that when you have a clot
24:31there and we're testing things
24:33that remove clots will likely
24:34going to have a positive outcome.
24:37Whereas we include patients
24:38that don't have a clot there.
24:40And we're testing the clock removal device,
24:42it's going to be harder to find a benefit.
24:45And then eventually,
24:47we'd like to enable personalized
24:49rehabilitation therapy for the long term.
24:52So the primary objective is to validate
24:54the most promising biomarkers and
24:56motor recovery after ischemic stroke.
24:58In this first large scale perspective,
25:00generalized data set.
25:01So the idea is 557 ischemic stroke patients,
25:05but they also want to collect and we
25:08want to collect data on hemorrhage
25:09patients and exploratory factions,
25:11so they'll be 100 intracellular
25:13hemorrhage patients as well.
25:17So what is the first biomarker?
25:19Well, the first fire marker is trans
25:22magnetic stimulation of the escalation,
25:24absolution or motor cortex.
25:26So you stimulate it and then you see
25:29if you get a motor evoked response
25:31in the extent to carpi radialis
25:34and the first dorsal interosseous,
25:36and that MVP plus means yes,
25:39some of those pathways are
25:40intact if you stimulate it,
25:42you get a response and it means you
25:45have a functionally intact system.
25:48The second biomarker is looking at the
25:51cortical spinal pathways themselves,
25:53and looking at the DWI lesion
25:56load along that pathway,
25:58and basically the more lesion you have,
26:01the more structural damage and Jelly
26:03the poor you're probably going to do.
26:07So here's hypothesis,
26:09aimed 118 is to look at the
26:12relationship between the upper motor,
26:15upper extremity motor impairments were
26:17baseline in 9090, days after stroke.
26:20The upper extremity was called
26:22defense score and and it's going
26:24to depend upon whether it's
26:26your MVP plus or any P negative.
26:28Whether you have a motor
26:30response but transmitting exam,
26:32and here are some actual data
26:34where you can see here that those
26:36that have a positive response.
26:38Are much likely to have a good 90
26:40day upper extremity film score,
26:43and those that don't have a positive are
26:46much less likely to have a good score.
26:52Also, we're going to look at the
26:54relationship between MRI measured
26:56the lesion volume and the 90 day
26:59opportunity motor impairment,
27:01but how it reflects and depends
27:03upon the MVP, the stimulation.
27:05So here's some more data
27:07where you can see that yes,
27:09the more you lesion load you have
27:11the jungle worse you do at 90 days,
27:14but if you got an intact
27:16stimulation response while there's
27:17still a little bit of a decline,
27:20it's a much better response.
27:22Then it is when you don't have a response.
27:28Hypothesis 2 is they're going to use a
27:30Prep 2 prediction tool which will try to
27:34accurately predict the likelihood of a
27:36good upper extremity functional outcome.
27:38That's decide defined by the
27:41active research ARM score,
27:43and they're going to be able to do that,
27:45hopefully for more than 70% of patients.
27:47And so here you see that they use
27:49something called the safe score.
27:51Safe Score is a shoulder abduction
27:54finger extension extension score,
27:56and the higher the score, the better.
27:58More likely to have a good outcome.
28:00So if you're more than equal
28:01to five and you're young,
28:03it's really going to be doing pretty
28:05well predicted by this score.
28:06If you're not as young,
28:08well then and you have to divide
28:10up a little bit differently.
28:12You may tend to fall a little bit.
28:14Not quite as good, but still pretty good.
28:16If you don't have a good baseline score,
28:20but you got intact magnetic
28:23stimulation response,
28:25generally you still may fit up in
28:27a good response, but if you don't,
28:30and depending upon how severe
28:32stroke scale score is,
28:33you also fit into these categories,
28:35so it's idea is trying to put people
28:38in categories within a couple days
28:41of admission to the hospital.
28:46Here are the key eligibility criteria.
28:48So age 18 years older unilateral stroke
28:51due to ischemic or hemorrhage and the safe
28:54scores gotta be lasted an equal to 8,
28:56because if it's more than eight,
28:58you're generally gonna have
28:59a pretty good outcome.
29:00And this also excludes full or nearly
29:03full motor strength in both the shoulder
29:06abduction and finger extension.
29:08Key thing is you gotta get them
29:11consented within 48 hours to 96 hours,
29:13so here's a biomarker study or
29:15recovery biomarker study that's really
29:17a lot like an acute stroke study
29:19and that we're trying to get people
29:21involved within the first few days.
29:26Here are the different aims and I'm
29:27not going to go through this in detail,
29:29but just to point out the different.
29:32Measurement outcomes to address each
29:34aim so the upper extremity of people
29:38Myers scale the upper motor action
29:41research arm test the motor activity
29:43log score and then looking at all of
29:46these aims and these outcome measures
29:49with intercell hemorrhage as well.
29:54Again, that first day visit getting
29:57consent within 96 hours and then
29:59some also visits that occur very
30:01quickly with a lot of assessment,
30:04which means you got to get an MRI of the
30:06brain and the transmitting stimulation
30:08and the participants only enrolled if
30:11they've gotten the TMS stimulation
30:14or they've had the MRI sequence.
30:17And then we look at any adverse
30:20events following that stimulation,
30:23and then we do a day 30 visit
30:26and a day 90 visit and the study
30:28essentially is over a day 90.
30:32So. It's moved very quickly.
30:34We just got the award in September.
30:37We're making a lot of progress.
30:39We've also just put in the request
30:41of the purchased as the medic
30:43Magnetic Stim devices for the sites,
30:45and the idea is we would hopefully
30:48be having sites ready to be trained
30:51in spring and maybe enrolling
30:53the first patient by summer.
30:56And just a few comments about this trial.
30:59It's a really A to biomarker study.
31:02It's not a trial where we're
31:03doing intervention,
31:04so it actually you can enroll
31:06people in this trial while also
31:09being in other trials because it's
31:11not affecting the outcome per say.
31:13And this will be a decision
31:15by other Pis of other trials.
31:17How much overlap?
31:19But there's no,
31:20there's no ethical reason or
31:22statistical reason why people
31:24couldn't be in both trials,
31:26so again,
31:26this will be hopefully happening very soon.
31:32The last time we talked about is Rhapsody 2,
31:35which again should be coming
31:37in 2022, probably later.
31:39It's a neuroprotective trial in setting
31:41of patients undergoing re profusion
31:43therapy within 24 hours of onset,
31:46whether by a lytic drug or
31:48by end of vascular therapy.
31:51It was approved by council in 2021.
31:54It also has gotten approval the
31:57CRB and FDA is also approved the
32:00protocol pending a few outstanding
32:02items and the company is gearing
32:04up to manufacture the drug at the
32:07SIBO and it is a global trial
32:09and the outside of U S sites.
32:11They're also submitting their regulatory
32:12documents and grant applications,
32:14so big trial in a lot of places.
32:19So what is the neuroprotective agent? Well,
32:22it's a mutated form of activated protein C,
32:26and those who remember clotting cascade
32:28activated protein C is important part
32:31of anticoagulation within the blood.
32:33But if you replace 3 lysine residues
32:38here with three alanine residues,
32:41it basically eliminates almost
32:43all of the anticoagulant activity,
32:46but preserves cell signaling activities.
32:49So what are those?
32:51Well, there's several.
32:52It can be vascular protective
32:54at the end of helium and helps
32:57stabilizes the blood brain barrier.
32:59It affects neurons and that could be
33:02under protective effect with neuronal
33:04function and promotes neurogenesis.
33:06It's anti-inflammatory and again
33:08the mutant form has very limited,
33:11a much lower amount of any
33:13coagulant activity.
33:17There was a phase two trial of
33:19this agent done as part of the
33:21neuron next network and I just
33:23showed you the bottom line here,
33:25which showed that in patients
33:27who got the active drug,
33:30the mutant APC there were less
33:32bleeding in the brain of an
33:34ischemic stroke compared to
33:36placebo as measured by MRI.
33:41So the primary aim of this trials
33:43to evaluate the safety and efficacy
33:45of the mutant APC for acute ischemic
33:48stroke looking at the orbital shift
33:50analysis at the three month time
33:53window and the key secondary outcome,
33:54is the proportion of patients
33:56alive and without interest.
33:57Several hemorrhage at 30
33:59days after ischemic stroke,
34:00that incenses, our safety outcomes.
34:04So those are three new trials,
34:07but now I'm going to switch gears
34:09and talk about platforms and I can
34:11ask how many people have had dove
34:14off a high board before and I have,
34:17but I've never done it at those big
34:20platforms that are 30 or 100 feet
34:22high and and that seems pretty scary,
34:24but the higher the platform,
34:27the more you can do before you hit the water,
34:29whether it's you know four twists
34:31or four turns.
34:32Whatever you watch the Olympics,
34:33you see that.
34:34So we're talking about platform trials.
34:36It could be a little bit daunting,
34:38a little bit scary,
34:39but there's a whole lot of things
34:42we could accomplish by the time
34:44we finished the platform trial.
34:47So let's talk about why this platform
34:50trial is happening in stroke.
34:52Let's go back in time to 2018,
34:54where Diffuse Three was finishing up.
34:58Don was finishing up,
34:59and there was such excitement in the field.
35:01It was only a couple of years before that,
35:02and they've asked her trials were
35:04positive was really geared up,
35:05and lots of people had lots of ideas,
35:08and so there was this plethora of trials
35:11that are being proposed and sent to an INDS,
35:14and you can see them here a lot.
35:18And you can see the one by the domain of the.
35:21Those that were kind of expanding.
35:23The indication new things added and
35:25then system kind of type type trials
35:28like in the prehospital setting.
35:30Well, and I and D as responsible
35:33to fund a lot of things and a lot
35:35of stroke thinks and they can't
35:37just do endovascular trials.
35:38They said, well, Gee,
35:39we can't just do all these in the
35:41back massacre trials proposed
35:43would be doing nothing.
35:44But is there a better way to answer
35:48the questions that are being proposed?
35:51So here is the current approach.
35:52Back in back, several years ago, Mr.
35:55Clean comes out and says hey,
35:56we know endovascular works in alternately
35:59population and we have done and diffuse.
36:02Well,
36:02that's still work.
36:03We were treating a little later
36:05if we can select out patients
36:07by imaging and clinical exam.
36:09And then you can do another
36:10trial and another trial,
36:11and it keeps extending the indication,
36:13but it takes longer and longer
36:15and longer to get it done.
36:17So Janet Woodcock,
36:19the FDA in 2017 said,
36:21you know our clinical trial system
36:24of kind of just doing one trial after
36:27another is broken and we need a new ways.
36:30And she noticed used to master
36:31protocols or protocol for trials
36:33where you look at multiple therapies
36:35for single disease or single
36:37treatment and multiple diseases and
36:39new platform or neutral networks
36:40really are the future of where we
36:43need to go with clinical trials.
36:46And there's several different
36:48types of trout platforms,
36:49so there's an umbrella trial.
36:52I'm going to type platform when you have
36:54multiple treatments for one disease,
36:56and that's actually one of those
36:58had been proposed earlier in stroke
36:59net for very for neuroprotection,
37:01there's basket trials where you have
37:04multiple diseases of one treatment.
37:06Let's say we're going to look at a
37:08traumatic brain injury, intercell,
37:10hemorrhaging, ischemic stroke,
37:11and using our protective agents,
37:13just for example.
37:14Minesweeper treatment as you
37:16got one treatment, one disease,
37:18but you're trying to identify
37:20multiple subgroups.
37:21Big strokes, small strokes,
37:23strokes of a certain nature,
37:25certain certain type of population.
37:28That's the minesweeper approach,
37:29and that's kind of what we were
37:31trying to get at with some of these
37:33trial proposals back in 2018.
37:38So here's our FDA guidelines.
37:40Guidances that came out about how to do
37:43these trials and and a lot of it started
37:46out quite frankly in the cancer area.
37:48In fact, you can see them then the platform
37:52trials really started in the cancer
37:54area back in 2005 with prostate cancer.
37:57They've done a lot of
37:59patients since that time.
38:00The I spy, two with breast cancer 2010,
38:04but then you can see it starts to
38:07accelerate here in 2019 for glioblastoma.
38:092020 for a less 2020 for pain and that.
38:14Here, hopefully in 2022, four stroke.
38:19So one of the advantages of master
38:22trial protocols well eliminates the
38:24cost and duplication of resources
38:26with traditional freestanding
38:27parallel group randomized trials.
38:30It has some of the.
38:32Advantages of the stroke net that
38:33we talked about at the beginning.
38:35You can have the infrastructure in
38:36place and just keep adding things in.
38:39You can also compare multiple invention
38:41interventions crossarms you can
38:43look at subgroups of patients with
38:45distinct or related clinical features.
38:47You can minimize downtime between
38:50trials you share control groups,
38:52you drop arms early when treatments fail
38:54and you combine promising treatment arms.
38:59So an idea said this is where we want to go,
39:02so we're going to put out a special
39:05notice of interest to do this for stroke,
39:08and so a number of the investigators
39:10in stroke net took this on and actually
39:13recruited people from the field as well.
39:16You know, from the end of Ascot community
39:19in general to put a really terrific team
39:21together and and put an idea of how
39:23we want to do this that was submitted.
39:25We've gotten some great feedback on that,
39:28and I think the future looks bright.
39:30For having this happening,
39:31hopefully you know starting this
39:33in some phase of things in 2022.
39:36So here's the step platform.
39:40So it's made up of three components,
39:43so the stepstone or sort of like what
39:46extension of endovascular therapy should we.
39:49Looking at small stroke scale scores,
39:51big chords, other potential options.
39:55Step Smart is how can we add
39:57something to this,
39:58whether it's a new drug or protective drug,
40:01a new device,
40:02a new way of doing,
40:03let's say anesthesia couple different
40:06things are in this step smart
40:08and the step lively is.
40:10How can we do companion trials
40:12that maybe look at systems of care
40:15identifying these patients in the field?
40:17Again, a range of opportunities,
40:20but all trying to focus on patients who
40:22have a clot in an artery that we can
40:24see that we want to do something about.
40:30The other idea about this,
40:32we want to take the databases
40:34that we're already collecting
40:35and maybe build off of those,
40:37rather than creating a whole new database.
40:39So make it easier on sites to already
40:41take the data they're collecting
40:43and use it for these trials as well.
40:48Here's a little bit of
40:50these overall organization,
40:51and you can say it's pretty extensive.
40:54You have your executive committee
40:55and operations group here,
40:57but there's the group that
40:59worked on the actual kind of
41:01trial ideas and systems of care.
41:03But then there's a whole bunch of
41:06corps recruitment data imaging,
41:08and the vascular quality statistical core.
41:11And then it's all still connected
41:14with the stroke net organization and
41:16it's overseeing again by the DSMB.
41:19And the central IRB. And again, it's a.
41:23It's a great infrastructure and we
41:26hope to get it started here soon.
41:29So let's talk about what's the first step.
41:31Well, the first step is to get the
41:34database in place and the entry of
41:37patients who have a visualized clot in
41:40the artery with an ischemic stroke.
41:42That's eligible for endovascular therapy.
41:45That's kind of what we were
41:47looking for to start with,
41:48and then we start adding in their respective
41:52trials into that baseline infrastructure.
41:55So again,
41:57expansion into different areas.
42:00And then the rest is really work
42:02in progress and and people are
42:04working very hard and let some great
42:06ideas already out there with the
42:08posed with from our stroke net.
42:10Colleagues throughout throughout EU.
42:12S.
42:14So that's what's coming to us,
42:16but I I wanted to just talk about
42:18some of the challenges again
42:19that we've faced as a network.
42:21All of you have been through this,
42:22so first one is COVID and
42:24it's still a challenge.
42:26It's still affecting us in multiple ways
42:28in getting patients enrolled in trials,
42:31and I think it's going to still be
42:33like that for at least this next year,
42:35but hopefully it will subside and
42:37the stress of COVID will have made
42:39us a stronger and better network.
42:42There's other,
42:42though challenges about how we interface
42:45with our colleagues in other specialties,
42:47particularly cardiology
42:48and Kevin and colleagues.
42:51With this fire and Maggie
42:53and colleagues would Saturn.
42:54I really struggled with the fact
42:56that cardiologist had some very
42:58definite ideas about how their
43:00patients should be managed.
43:01For example,
43:02you know everybody should be on
43:04a statin if they've had a cardio
43:06cardiovascular problem and what
43:08they don't understand is that
43:09it may not be the same formula.
43:11For patients who have very
43:13specific issues such as low bar,
43:15icah and so we need to educate them,
43:19we need to have conversations with
43:21them and we need to publish in order
43:24to get that equipoised among our
43:26cardiology colleagues and not just ourselves.
43:29The other thing is that I see patients
43:31who are very severely affected
43:33and so enrolling these patients
43:35adventure trials is harder than it
43:37is for most of these key mix trucks,
43:39and we're looking at many
43:40different ways to approach this.
43:42Spanning are expanding
43:43our inclusion criteria,
43:45but also how we go about
43:47enrolling these patients.
43:49Another big issue with acute
43:51trials is recruitment of patients
43:54outside of business hours.
43:56So in the most trial,
43:57recently took a survey and found that
44:00just about a little bit more than
44:02half of sites were only recruiting
44:04subjects during Monday through Friday,
44:06Monday and business hours and their
44:09enrollment rate in the trial was
44:12about half that of those sites that
44:15recruit outside of those those days and 24/7.
44:18So we need to find ways to address this.
44:22How to address this call?
44:23It's an expensive to Burditt,
44:25but if we're going to be successful
44:27acute stroke trials and recruitment,
44:28we didn't need a whole bunch
44:30more sites or we need the sites
44:32that are up most of the time.
44:35I think though the biggest
44:38challenge I think with COVID.
44:40Relates to the overload burning loss of
44:42study coordinators across clinical research.
44:45In general. It's not just for stroke,
44:47but for all of us.
44:50What's happened here is though,
44:51people get burned out and then you
44:54have to recruit a new coordinator,
44:56and that person is less experienced
44:59or you can't find a new coordinator,
45:02so they'll coordinator that was doing
45:04three trials is now doing 5 trials,
45:06which then leads to them getting burned out.
45:08And also maybe not as good a follow
45:10ups and doing the follow ups at
45:12three months and six months because
45:14they're trying to do 5 trials,
45:16or the three.
45:17And so this is a really big issue.
45:20Is not anyone great solution to it?
45:22We've actually surveyed the
45:24coordinators and most of you have
45:26probably filled something like this
45:27out over the last week and we're
45:29going to be talking about a webinar
45:31next week for stroke that about what
45:33the data shows and talking about.
45:35Maybe some also potential solutions.
45:40For those of you who maybe
45:42who like movies and when.
45:43I look at some cool videos,
45:45either the trials,
45:46the trial leaderships have come up
45:49with some really cool innovative
45:51videos of how to recruit patients,
45:53explain trials,
45:54explain exception from informed consent,
45:57how to train people and to
45:59enroll people in trials,
46:01and so if you've got a chance,
46:02go on our website,
46:04you will see the the respective
46:06videos on their respective trials,
46:08and there's some really good I think.
46:10Ideas there,
46:11and if you're planning a trial,
46:12this is a great place to start
46:14to see how you can do this well.
46:19The last thing I'm going to bring up
46:22is that it's not just about stroke net.
46:26We are we have a global problem stroke
46:28and we need all of our colleagues from
46:31around the world pulling together
46:33to solve these questions and one
46:35of our goals at the beginning and
46:37I stroke networks establishment.
46:38The global network of national
46:40stroke networks and working with our
46:43colleagues in Canada and UK and Europe.
46:45Initially we begin the gains network and
46:48we have a website which link is there.
46:51It's been a terrific forum for
46:53discussion of potential trial proposals,
46:55educational efforts for development,
46:57young investigators,
46:58and planning for the future of
47:01collaborative stroke research.
47:02There's actually 23 national
47:04global networks that participate.
47:06Currently,
47:07we have regular recording meetings
47:09of the Executive Committee,
47:10as well as in person,
47:11which was prior to COVID and
47:14virtual meetings for Members,
47:15and we actually have a forum where we
47:17talk about new trial ideas globally,
47:20or when people are looking for
47:21other countries that may want
47:22to participate in there.
47:23File,
47:24and that's really been been
47:26actually great sessions who all
47:28welcome to that that's published
47:31and publicized through stroke net.
47:32So if you want to listen to that,
47:34you have here some really good
47:36interesting ideas for the future,
47:37and we've already moved to several
47:40global trials within stroke debt.
47:41Arcadian, Saturn.
47:42Both had Canadian sites and
47:45the improved Rhapsody too,
47:46as well as the ongoing fastest
47:49trial or global trials.
47:51So, just to summarize,
47:53political stroke networks are the present
47:55future of clinical stroke trials.
47:58You don't have to restart a network
47:59every time a new trial is proposed.
48:02But there's always things that happen.
48:04We need to be flexible and nimble.
48:05Response to events like COVID.
48:08There'll be other things in the future,
48:09hopefully like COVID,
48:11but you always know there's
48:13something that will happen.
48:15We can answer clinical stroke
48:17questions better and more quickly
48:18with global cooperation in isolation,
48:21so that's one of our future goals
48:23as a network and as our global
48:25connection of networks.
48:27But exciting new trials are
48:28coming to a site near you,
48:30and we also look forward to exciting
48:33new ideas for trials from our RCC
48:36sites throughout the country.
48:37I think we've got a great pipeline.
48:39We've got great people and just just so
48:41proud to be part of this wonderful network.
48:43Thank you so much.
48:45Joe, thank you so much for that.
48:47It was an amazing overview of
48:49what's coming up through stroke net.
48:51I don't see any questions in the chat yet,
48:53but I encourage people to put
48:55them in if they have them.
48:57Joe, do you see the network expanding
48:59as all of these new trials come online?
49:03I well you you have to ask me and I
49:05and DS but just to give you an idea,
49:08what's happening is NINDS is
49:10doing an external review of all
49:13of their different networks,
49:15so next which many of you also apply
49:18part out and and I stroke net are the
49:20two that are being looked at right now.
49:22And believe me we give them more
49:24data than they probably have been
49:25like drinking from a fire hose and
49:27what they're going to try to do
49:28in this committee is saying paper
49:30what's working well and what and
49:31what do we is a network feel like it?
49:33Working well and what would we like to
49:36do better and and how do we solve some
49:39of the issues like the coordinated burden?
49:41You know?
49:42How do we support people to get
49:44recruitment more effective?
49:45So I I don't think will probably
49:48change the number of Arc they could.
49:50Maybe add one or so besides 24,
49:53maybe get back to 25,
49:55but I don't see that changing.
49:57I think the number of sites we
49:59already had 280 and we don't really
50:02utilize all those 280 as well.
50:04As we could,
50:05but I think the expansion will be if
50:08we do something is how we coordinate
50:10with other networks and that is.
50:13That's a challenge because you
50:14have to figure out how you get
50:16money from different sources in
50:18different countries that can be
50:20approved to do the same project,
50:21and so that's something
50:22we've been struggling with.
50:23As in the game's leadership group,
50:25but I think that would probably be the
50:28biggest potential for maybe expansion.
50:32And I have a.
50:34It's a rather provocative question,
50:35but when you showed that slide
50:38of other platform clinical trials
50:41in a myriad of other diseases.
50:44You know, it just seemed to me
50:46that those are still diseases
50:48that we don't have effective
50:50treatments for in many cases.
50:52Can you or are there any success stories
50:56from from that platform approach?
51:00I think that the adaptive adaptive trials,
51:03which is kind of a little bit of a platform
51:06had been very successful in cancer.
51:08I think they that's where that's been.
51:11Some of the newer ones are.
51:12They're only you know, a year or so old,
51:14so we don't know how they're going to
51:16pan out like prickly blastoma or pain.
51:19But I I think the future is bright,
51:22but we won't know.
51:23I think for another ten years,
51:25how some of those other
51:26things are going to workout.
51:28You really need a.
51:29You need a 10 year time.
51:30Window to see how I platform is.
51:32Actually I think you know doing.
51:35I I will anticipate the one of the things
51:38you were talking about is that with
51:40stroke we've gone from an untreatable
51:42disease 12 highly treatable disease,
51:45both acute and prevention,
51:48and now even recovery.
51:50We got a really exciting to do paper
51:52that just came out from one of our
51:55members who out stronger Coop past.
51:57But I mean what?
51:58What a legacy to have such a paper
52:00that came out within just a few weeks
52:02of you know him passing but there's
52:04a lot of excitement in recovery.
52:07We and this is my opinion.
52:09This is not anybody else's opinion,
52:11but.
52:12I think we're going to come up,
52:13get up against biological limits
52:16for acute just like in cardiology.
52:18If you look at cardiology,
52:19there hasn't been a major acute advance
52:23beyond the RE perfusion that we
52:25talked about for probably 10-15 years
52:28and we're still in the Golden Age,
52:31so we're going to get better and we get
52:33more extension and identify groups and
52:35maybe add things that can improve things.
52:37But you know,
52:38I do think there's a timeline on that,
52:40and maybe you know 1015 years.
52:43So which at point at which point
52:46defined the small tiny benefit?
52:48She would need tens of thousands
52:50of patients which we need to have
52:52to have huge big global trials.
52:54I think prevention, we still are.
52:57We still learning.
52:58We probably a little bit more opportunities,
53:00but we're still.
53:01We've made a lot of progress
53:03there and and a lot of it is
53:05changing our lifestyles as much as
53:07adding another another drug and.
53:08And that's a hard thing to do.
53:11I think the biggest timeline is recovery.
53:13I mean,
53:14we there's so much we're learning
53:15about how the brain recovers,
53:17and I think that has a much larger timeline,
53:20quite frankly, but that's just my opinion.
53:27A question from Shadi.
53:31Do you anticipate that the platform
53:33trial design will be used for
53:35prevention and recovery trials as well?
53:37Hi hi uhm. And probably probably not I,
53:44I think with anything you want to
53:46first Test something out and in.
53:48In some respects the platform was
53:51in response to this overwhelming
53:53excitement and number of proposed ideas.
53:56In the end of Vascular area,
53:58which they and some of those trials are going
54:00on independent actually funded by industry.
54:03I don't think that, but if it turns out
54:06to be a really good successful situation,
54:09then you know, but it's.
54:10The fundamental thing is
54:12endovascular treatment.
54:13Things added with preventions,
54:15you're often talking about
54:17different population of patient,
54:18different subgroups.
54:19That makes it harder, and so I think it
54:23would be more of a challenge I recovery.
54:27That may be placed in the future.
54:30We could go to.
54:31I think I would say more recovery than
54:34prevention just at first question.
54:36It's really good question,
54:37shoddy,
54:37but that's just kind of my
54:39gut reaction to that great.
54:42Alright, I'll hand things back over to Shadi.
54:48Hey, thank you so much Doctor
54:50Broderick and Doctor Furey.
54:52We've had very informative presentations
54:54and excellent discussions so far.
54:57This now brings us.