Judith: Welcome to Berry's In the Interim podcast, where we explore the
cutting edge of innovative clinical trial design for the pharmaceutical and
medical industries, and so much more.
Let's dive in.
Scott Berry: All right.
Welcome everybody.
Back to, in the interim, I'm your host, Scott Berry, and today I have
three guests and we're gonna talk about a new adaptive platform trial.
And the, the trial name is Panther and we'll get to what, what Panther is.
But, uh, let me introduce you to our guest today.
First, I have Professor Victoria Cornelius.
She's a professor of medical statistics and trial methodology, and the director
of the Imperial Imperial Clinical Unit and co-director of the NIHR Research
Support Services, Imperial College London.
And she has extensive experience in designing and analyzing trials to
evaluate drug and complex interventions.
And uses, uh, both Bayesian and Frequentist adaptive designs using
innovative statistical, uh, approaches.
And we will talk about those today.
Uh, we also have Dr.
Danny McCauley, who is a consultant and professor in intensive care
medicine at the regional intensive care unit at the Royal Victoria Hospital
in Queens University in Belfast.
He is the NIHR Scientific Director for research programs.
He has several research interests, including acute respiratory distress
syndrome, which will be a topic for today, uh, as well as recovery following
critical illness, uh, in clinical trials.
Danny and I have worked together, by the way, extensively on the REMAP CAP
trial, a different trial that, uh, uh, isn't the main topic, uh, of today.
And we have Professor Anthony Gordon.
Uh, uh, professor Gordon is the head and of the division of Anesthetics
Pain Medicine and Intensive Care at Imperial College London.
He is a consultant, uh, on the adult intensive care unit at St.
Mary's Hospital and is an NIHR Senior investigator.
His research focuses on developing precision medicine and sepsis.
And he's been the chief investigator for multiple clinical trials in critical care
and he's now the director of the UK's NIHR Health Tech Technology Assessment
Program where he's keen to encourage innovative and novel trial designs.
And I think we have a pretty innovative and novel one today.
Uh, and Tony is also a member of the most excellent order of the British Empire.
Uh, and I've also worked quite a bit, uh, uh, for a number of
years with Tony on remap Cap.
We've all worked together, so welcome everybody to in the interim.
Anthony Gordon: Thanks Scott.
Danny McAuley: Thanks Scott.
Scott Berry: all right, so Panther.
Uh, Panther is a new platform trial, and I, uh, I should say that I am a member of
the DSMB and I'm honored to be a member of the DSMB, but we have seen no data yet.
So I'm not unblinded, there's no risk that I'm going to give
away results in the trial.
Uh, somewhat familiar with the trial, but, uh, uh, so this,
that'll be a, a fun part of this.
So the, the Panther platform trial, uh, and it, it labels the objective of
this is to accelerate the development of pharmacological therapies for
critical illness by establishing an international phase two precision
medicine adaptive platform trial, uh, to test for efficacy, uh, in.
Uh, pharmacological intervention in critically ill patients for acute
respiratory distress syndrome and pandemic infection and different sub phenotypes.
So tell me about the Panther trial.
First of all, why, why do we need the Panther trial?
What is the Panther trial trying to address and solve?
Danny McAuley: Thanks, Scott.
I'm happy to kick off and we'll see where, uh, we, we land with Tony and Victoria.
So I, I guess in terms of what we're trying to do, uh, there are several
challenges, um, in treating, uh, a RDS.
Um, there's a huge amount of heterogeneity within the, uh, overall population.
Um, and I think.
More recently, over the last sort of five to 10 years, we've recognized
that there are phenotypes that exist within these, uh, syndromic
definitions of, of conditions that we deal with in intensive care.
Like IRDS the most consistently reported, and there are others Tony may wanna
pick up on, um, are the inflammatory phenotypes that are, uh, described
originally by, uh, Carlin Calie.
Over now, 10 years ago.
Essentially, these now have been replicated in multiple,
uh, secondary analysis of RCTs, observational cohorts, adult kids.
So we're trying to get at that heterogeneity by focusing on, on
those phenotypes, and we've only recently been able to identify.
Those at the, the bedside, which we can come back to.
So that's one big, um, thing that we're trying to deal with.
The second, uh, big issue is that I think traditionally in, uh,
critical care, and particularly ARDS we've jumped from relatively
small promising phase 2 studies.
into Big phase 3 Um, what we're really trying to do with, uh, Panther
is give confidence in the therapies that we think might work, uh, with a
much greater amount of, of certainty.
So move from small phase 2 to big phase 2 within, uh, Panther.
And then I think that the other issue is that, um.
We've really struggled to get, uh, uh, commercial partners engaged
within, uh, the critical care space, particularly within ARDS
and sepsis, largely because of a.
Con misconception, I think that, um, uh, ARDS and critical
illness are are a, a graveyard.
And I think what we want to try and do is de-risk the involvement with
commercial partners because we have an established ongoing platform that we can
hopefully answer questions that, uh, help.
Commercial companies, uh, at a sort of, uh, lower risk, but uh,
also more importantly and perhaps most importantly, help patients.
So I'll, uh, stop there and see what others have to say.
Anthony Gordon: Yeah, Scott, I think obviously.
Align with Danny's thinking.
I think it's, we've got critically ill patients.
There's this unmet need to improve their outcomes.
So these are patients at high risk of dying.
provide them generally with supportive care, but when it's come to trials
of specific drugs that might, uh, modulate, for instance their immune
response to that critical illness, promising drugs from preclinical studies
haven't translated into that benefit.
And I think it is because we've.
As clinicians, we group patients with similar signs, symptoms,
organs that aren't working.
So in this case, lung injury,
given them the treatment.
And probably some of those treatments have had potential for benefit.
But in the trials we've just not seen it because there are others who don't benefit
and probably some, uh, that are harmed.
And as Danny said, there's been a big emphasis in actually.
Breaking down these clinical syndromes into more biological sub phenotypes.
And then it would seem that the drugs, if you could target the biology,
are more likely to be beneficial.
And so with this, um, if we do that though, it needs to
be, uh, a joined up effort.
International is the other aspect of this.
If we try and do this on our own, because we're.
Breaking down the populations into smaller groups.
Um, we think the important thing is to come together so that we can work
internationally, get answers more quickly.
Um, so that is the other key part of this being an international,
uh, platform, getting the key investigators to work together.
Scott Berry: Oh, okay.
So it, it, it's an area, A RDS is an area that not much has worked in, and
yet it's still a clinical problem.
It's, it's, I don't wanna call it a, a graveyard, but
it's been a challenging area.
And you think to some extent, part of the challenge is ID not all a RDS is the same.
And so it may be some treatments, precision medicine, treat some
of them well, but others that may be negative and the net.
You run a trial, it looks like nothing but so this trial can try to
address heterogeneity of effect, uh, within this, do it in a larger scale.
An aspect of the platform, I imagine is easier shots on goal.
So if you've got this up and running and you want to bring in a treatment from a
pharmaceutical company or anything to, to take that shot on goal, to give it
a shot to investigate it, much cheaper, much smaller than going out and building
a whole new stadium to test that one.
I imagine that's why the platform part of this is, is interesting.
Anthony Gordon: Yeah, I think that's right.
And when you put it like that, there's maybe COVID-19 gave
us some of that learning and has helped to accelerate that.
This work was going on already.
But we saw the benefit of platforms of bringing in drugs
rapidly and getting answers.
But I think also just underpins the biological rationale behind this.
Uh, with COVID, a new infection, um, was essentially a RDS, um,
but very homogeneous, particularly at the beginning of the pandemic.
And that homogeneity, I think, was.
What enabled us, um, you know, multiple groups of trials to show, uh, the
drugs that were successful in immune modulation, uh, drugs, particularly
in the critically ill, uh, population.
So that sort, I think, reassures us that, that the biological rational is
solid, that we can improve outcomes if we identify the right patients with the,
uh, right underlying biology, uh, with these therapies.
Scott Berry: Yep.
Alright, so before before we move forward, a RDS, um, we've heard the term, you
know, what, what is a RDS and I know you talked about the heterogeneity.
So I mean, what is, what is a RDS.
Danny McAuley: So, uh, essentially, um, a RDS is severe, uh, respiratory
failure that is, uh, not due to.
Other recognized conditions like heart failure or, uh, fluid overload.
Um, and it's characterized by, you know, x-ray changes that are sort of bilateral
patchiness and severely impaired, um, lung function that we, um, uh, sort of
measured using measures of oxygenation typically, um, tho those people are on a.
Mechanical ventilator, although, uh, more recently the, the sort of syndromic
definition has been updated to include, um, people who are receiving high flow
nasal oxygen due to the increasing and, and widespread use of that.
So, so that's the syndromic definition.
But I guess, you know, as you might imagine, that sort of is
underpinned by a whole raft of different biological processes that
we're really only now starting to.
Get at, which is the sort of move to precision.
Scott Berry: Hmm.
Hmm.
Okay.
And, and you could this acute failure, so this is, uh, as opposed to as
chronic, uh, uh, in a particular way.
So some, some particular event has caused this respiratory distress,
and that could be sepsis cap and a whole wealth of other things that
get somebody into this acute status.
Danny McAuley: Yeah, that's right.
So I mean, if you get knocked over by a bus, you break your
leg, you have near drowning sepsis, you have bad pancreatitis.
So, and again, if you imagine the heterogeneity.
That as well, adding into the mix.
So it, it's not at all surprising that we, if we've treated all these patients
the same way that we've struggled to find a, a specific, um, therapy.
So I, I think again, that just emphasizes the need to, to follow the
biology and the then the phenotypes.
Scott Berry: Yeah.
Okay.
So there's this larger goal we, we, we should say, by the way,
so you're interested in this.
Panther platform trial.
And you've, you've presented this solution to a problem and
you have gotten this funded.
Uh, so who is the major funder of this?
Danny McAuley: So, um, the, the sort of first funder was the, uh,
national Institute for Health and Care, uh, um, research in the uk.
Um, I should say, uh, Tony and I also, uh, worked for the NIHR
as as well as, as you mentioned.
So, uh, just to, to mention that.
But we've now been, um.
Really successful in getting multiple other funders, which I think highlights
the, the sort of recognition of the, the importance of the unmet
need Were funded in the US and were by the Department of Defense.
Were funded in, uh, Canada by the CIHR.
We're funded, uh, in Australia now by, uh, a collaborative between
N-H-M-R-C and MRFF, and we've also got funding in Ireland from HRB as
well as, uh, Germany and, uh, Japan.
I don't think I've left any out there, but if I have, uh, but
Tony will correct me or Victoria.
Scott Berry: Yeah.
Okay, so we, we kind of understand that what, what we want this to solve.
And now this sort of comes to the clinical trial science part of it.
So how do we create something that solves some of these problems?
So maybe we should now talk about what the trial is, uh, the science of the trial.
So, Victoria, this is a platform trial.
Now, platform trials can mean lots of different things, uh, in this.
Uh, what, let, let's talk about the trial design.
What, what is the trial design now to help create some of these solutions?
Victoria Cornelius: Uh, yeah.
Thank you Scott.
It's uh, lovely to be with you here today as well.
Um.
So it is interesting that you said that platforms can be lots of different things.
Um, uh, I think, yeah, it, it would be good to talk about that and get your,
your opinion on whether they, how, how, how different those things can be.
Ultimately, we're talking about platform trials.
I think we're talking about, um, one area, one clinical area, and we're
talking about the ability to adapt things over time, to add in interventions and
to drop those interventions as well.
So that, that's how I would see it.
So some sort of adaptive.
Uh, trials design within, you know, o overarching, uh, structure.
Um, so with this, this is exciting.
Pan, pan is exciting 'cause we've got these, like I say, we're doing these,
uh, interest in these two phenotypes.
I dunno if we've named them yet actually as hyper and hypo
inflammatory, uh, processes.
Um, and we, what?
The, the overarching design actually is to stratify by, by these two sub phenotypes.
So I would call it a stratified, uh, trial, uh, adaptive.
Um, and within that, um, we are gonna be using, we've, we've chosen to do this
within a analysis framework as well.
Scott Berry: Hmm.
Okay.
So there's, uh, by, by the way, one of the fun challenges of these
podcasts is not having slides.
Uh, or you could have a slide that shows all of these components
together, but you have to sort of describe it to the audience.
So the platform part of this is you're gonna bring in multiple therapies,
and right now you have two of them that you have brought into the
trial and we can talk more about, but Simvastatin and Baricitinib.
So you have the two arms in remap cap, for example.
We might do factorial randomization, where you could get one or the other or both.
In this trial, I think at least now you've got this setup where you have parallel
arms, so you have a common control arm.
You can have simvastatin and Baricitinib, and when you add a new arm, it kind
of enters in this parallel way.
So a patient that comes in is randomized among.
Today, right now with the, with those two experimental arms, randomized
among those three possibilities.
Is that right?
Victoria Cornelius: That's right.
But stratified obviously with, because we are
doing it in the hypo inflammatory and the hyper inflammatory as well.
Yeah.
And we, yeah.
So it's not a multifactorial.
Scott Berry: Now, the, the, the sub phenotypes that you talked
about, the hypo and hyper.
Uh, so a patient that comes in.
So let's talk about the perspective of a patient.
A patient that comes in is the, the, the process of this.
So Tony, you see a patient, they, they fit the a RDS.
Inclusion.
Exclusion are the inclusion exclusion criteria for simvastatin
and baricitinib identical.
Anthony Gordon: They're very similar, so.
As a platform, we have inclusion exclusion criteria for the platform.
So as you said, it's essentially a patient with a RDS.
Um, there are then they're eligible for the, for the platform.
Scott Berry: Uh huh.
Anthony Gordon: Importantly it is then at that time they have their blood samples
measured and their assignment to the hypo or hypo inflammatory sub phenotype.
Done upfront before they're randomized so that they can then be randomized
essentially into the two strata.
Um, according to the, the sub phenotypes, the, the inclusion
exclusion criteria for each drug.
Um, as I said, I, I.
Virtually the same, but there have to be a few exceptions because
the drugs work in different ways.
So the obvious one is if you're allergic to one of the
medications, you can't have it.
But there are some.
For instance, with simvastatin, you have to be careful with drug interactions.
So if you're on another drug, you may be excluded.
There's concerns around patients with renal failure, for instance, that
would exclude you from Baricitinib.
But essentially they're the same.
And then.
Well those eligibility, once you know, the sub phenotype has been
determined, the randomization happens separately within each stratum, the
way you, the patient is allocated.
And so, as Victoria said, it's then a stratified trial.
Um, so the patients are in either one of the sub phenotypes.
Scott Berry: so as as a patient comes in, they're classified by the sub phenotypes.
Right now, I believe Simvastatin and Baricitinib are.
Uh, um, they're, they're getting patients from either phenotype when they start.
I imagine you could bring in a third arm where you already know
or think it would be, uh, uh, not good to test them in one of them.
And it could, it could, could come in, in only one, I assume, soon.
Anthony Gordon: It could in theory.
Um, um, and this is an interesting point.
We've had a lot of discussion around this, uh, particularly actually around
simvastatin, for instance, because.
The evidence from Danny's previous trial, maybe he should, uh, describe it.
Um, or maybe I should keep it shorter, that, uh, d Danny ran a, Danny ran a
previous trial, um, of Simvastatin in a RDS and in the overall population
didn't show any, uh, statistically significant benefit, but then.
Doing the, uh, sub phenotype analysis in a postoc way showed there was benefit
in the hyper inflammatory group, but not in the hypo inflammatory group.
So Danny and I particularly had the conversation about, well,
let's just go forward in the hyper inflammatory sub phenotype.
But I think a lot of people want to see both groups to understand
if there really is a difference.
And I think importantly, if you take the wider picture drug regulators.
Want to understand the effect I if in the two sub phenotypes to understand,
um, partly to know should have you recruited the optimal population, but
also what about safety, for instance, in the other group, if, if people
started using it outside of a sub phenotype, what would the effect be?
So we thought at this stage we, it was important to include them
in both, uh, sub phenotypes.
Um, at, at, at initial.
But whether that changes over time, I think it will be interesting as
new, um, drugs potentially come in.
But at the moment, yes, we're including them in both strata and want to analyze
them separately throughout the platform.
Scott Berry: Yep.
Danny McAuley: And I guess just to add a couple of bits, that the, the patients
were also really pain, that we didn't miss an effect in the other phenotype
where we, even though we expected it to work in hyper inflammatory,
and, you know, I think that's one of the things that we're, we're pain.
That the, the sort of design is underpinned by, uh, patient and,
and sort of public involvement.
Um, so that, that was actually a, a, another, uh, key piece of it.
Um,
Yeah,
Scott Berry: Yeah, so, so, so I think that's great.
And you, you said it's stratified by this, and that's one of those words that can
mean a whole bunch of different things.
Um, uh, whether it's the randomization, whether it's the analysis, but it
could be during the course of the trial and we'll get to the adaptive design.
That you stop enrolling one of the drugs.
So for example, suppose this bears out that simvastatin doesn't work in hypo,
and you, you could stop enrolling that in hypo based on the empirical evidence.
And then if a hypo patient comes in, they would only be eligible for the
control and baricitinib and not, uh, randomized to simvastatin at that point.
But yet, a, a hyper could be random.
To that.
Um, uh, so you're, you're, you're, this, this could be enrichment.
We haven't said the term enrichment, but you know, as you go along, you're,
you're learning this as well, uh, about.
Benefit or not within them That the, the, the, this is a case where you
don't, what the, let's talk about the control arm, the common control arm.
You're not using placebos here, so we're not doing double
blinding or multiple blinding.
So, uh, that pa you're not blinded to what the treatments
take, the patient is taking here.
And so control is standard of care, I assume.
Okay.
Alright, so we've got the, the this.
A patient comes in, they're classified by hyper and hypo.
They are then randomized among the arms that are enrolling, that
always equal across the arms.
Victoria, was there any thought of doing response?
Adaptive randomization, uh, in those cases.
Victoria Cornelius: Yeah, I mean, we talked about this a lot, uh,
during the design and in the end we decided not to use it.
So
we, we, we did consider it.
And it, and it's interesting actually, it, part of it was, uh, the, the thought
of around the operational side of these things, um, as well as only having
sort of the, the two active arms versus
the control as well, and not being convinced.
Of, of the statistical benefits as well.
So, uh, we, we chose not to do it, uh, to implement that.
Scott Berry: Yeah, no, I, I think that's, it's a really interesting question.
If you had six or seven and it was a pandemic scenario and you wanted to
accelerate drug one to the detriment of drug two, that might be more compelling.
I think here you're trying to find the evidence for a drug and accelerating
simvastatin and slowing baricitinib.
Probably doesn't make sense in what your trial is trying to do.
So I, I it's, and, and you don't want to add that complexity as you
described for not much benefit.
So I think that makes sense.
Anthony Gordon: Yeah, Scott, just to add, we, that's exactly it.
As you said, outside of a pandemic where there is no time urgency, um, this
is about comparing each drug against a consultant to learn whether it's.
A promising therapy that we can talk about what happens at
the end of this, uh, platform.
Because this is a phase two platform.
It's to identify promising drugs that would progress.
It's not about comparing different drugs, it's, it is working
out the efficacy of each drug.
And so therefore the efficiency of one, essentially one to one randomization
with the control is I think, um.
This, me saying it to some statisticians now, I think is the most efficient
design, um, to get your, your answers quickly for each individual drug.
And so that, that's why we're keeping it, that fixed ratio.
Danny McAuley: And I think the other thing, Scott, sorry Scott, the other
thing, Victoria might wanna come in.
You know, the way that we've set up the, the triggers to stop is that, you know,
you have to, you know, be convincing for efficacy, but we don't wanna prove harm.
So, you know, we stop relatively early if the signal isn't promising.
Uh, almost trying to back the winner type approach.
Scott Berry: Okay, so we've talked about what it looks like for a patient
going in now when an arm comes in.
So you have, you have a master protocol where when you bring
Simvastatin or Baricitinib or arm C in, it comes in as an appendix.
Let's talk about what that looks like from the perspective of an arm and maybe
even thinking about a pharmaceutical company that wants to put an agent in and
thinking about, okay, what happens to my.
My, my, my baby as it goes into this trial.
What is the, the design for that?
So the, the, the arm enters in and it wants to enroll in both,
uh, phenotypes, sub phenotypes.
What is the design for an arm?
Victoria, what does that look like?
Sample size,
Victoria Cornelius: Yeah.
So
Scott Berry: analysis.
Yep.
Victoria Cornelius: yeah.
So, um, this is, again, this is something we've been, uh, obviously
spending a lot of time on the current design with the arms.
And actually one thing of the things I did want to talk about, uh, with,
um, this design, because we are, we are, we are really lucky to be
doing this stratified trial, this
precision medicine approach is actually, in order to do that,
we've got to have devices.
And so one of the design considerations for the whole platform was that
the number of devices we can get, because that's gonna restrict the
number of centers we can include, is gonna restrict the sample size.
So that was So we've
Scott Berry: So sorry, can I, devices meaning ability
to identify hypo and hyper.
Victoria Cornelius: Yes.
Scott Berry: Uh, okay.
Okay.
Victoria Cornelius: so one of the very early design considerations is around,
around, uh, getting enough evidence for the phase two, doing that robustly,
as Danny had said, but actually just getting enough evidence such that
it, it's good enough to get through.
Right.
Let's test this in phase three.
So, So, we, so there is a sample size consideration there, so regard
to bringing in an additional arm.
I think part of that will be, have to come within the whole framework.
Of, uh, how far we are along with, um, the current two active interventions.
Yeah.
Scott Berry: So, uh, go ahead.
Victoria Cornelius: yeah, Sorry.
just to say it, so at, maybe if it came in now at the start, it would
have very similar considerations.
Um, but uh, later on we would have to redo and relook at those things.
Scott Berry: Okay, so a a, the, the design for Simvastatin, for example,
is it comes in and it's analyzed separately in hyper and hypo.
Uh, and maybe we'll come back to the question of, uh, borrowing or, or
independent analysis within there, but you've got an adaptive design that every.
Every three months, you do an interim analysis, and when a minimum sample
size is reached for that particular arm, it enters into the possibility
for stopping rules where it could be stopped for promise, or it could be
stopped for lack of promise, presumably, or it could hit a maximum sample size.
So if my arm comes in, it goes through these.
Quarterly analyses and, uh, the maximum sample size, just roughly,
uh, for, for an arm is what?
Victoria Cornelius: It's around about 505, I think.
5, 2 5.
For each arm?
Scott Berry: For, for each sub phenotype?
Victoria Cornelius: Yeah, for each arm.
Scott Berry: Okay.
So once it reaches that max, where, where we've got enough
information, this is phase two, but it could stop sooner than that.
And it can stop at different times within hyper and hypo.
And for different reasons, it could be promising and hyper simvastatin
if, if it reproduces a previous result and it could lack promise in
hypo, uh, as a potential within that.
Now, the, the analysis that done, uh, the, there's, there's a huge amount of question
in these, in intensive care type trials.
There's what's the endpoint?
Um, so what is the primary endpoint that is used for the determination of
promise or not promise for an agent?
Victoria Cornelius: Yeah, a, uh, a, a great question.
Um, so we had, uh, again, another thing we talked about a lot, um,
obviously we are trying to, the, the obvious one would be to use mortality.
Um, but we were trying to, we were trying to move beyond mortality
in these situations because.
We want something, um, partly because the statistical considerations around using
it, which we need thousands and thousands, uh, but also trying to get an, uh, sort of
capture an important part of the patient journey as well within the outcome.
So terribly inspired by the REMAP cap trial.
Um, we have got the primary outcome of 28 days of a composite
the same, but it's for 28 days.
Organ free support.
Um, so we've got our mortality being our minus one score and then, and
we've got it up to zero, up to 28 days.
Organ free support being the best outcome.
Scott Berry: Okay, so you described these ordinal outcomes where death is the worst
outcome, and then being on organ support for 28 days is the next worst, and so on.
And so you've got this ordinal outcome which you analyze
using a proportional odds.
Bayesian proportional odds model.
Yep.
Victoria Cornelius: Yeah, that's right.
Yeah.
Scott Berry: Okay.
And, um, I, and in a really interesting question, and I think it almost becomes
more interesting, part of what I found intriguing about the trial is you've got
an appendix for subphenotypes where the science may evolve, where you learn that
there are really important subphenotypes and you add them to the trial.
Right now you have two, and so you have this question when you analyze.
Um, uh, hyper and hypo.
You run a completely separate model.
Within each of these, and so there's no borrowing.
So if a drug is doing well in one and well in the other, there's no
kind of borrowing strength there.
Partially you're worried about heterogeneity, and that may
have the opposite effect.
This could be a bigger problem if you add another sub phenotype
to the trial that the question is then how do we analyze across this?
Was there any discussion about potentially doing borrowing
Victoria Cornelius: There, there was a lot of discussion about doing borrowing.
Um, philosophically I have a problem with that.
Like you say, we're actually out and we've got quite strong, you know, we've got some
underpinning evidence we're expecting.
Differential responses here.
So it feels, the premise of it doesn't feel correct and, uh, to, to be borrowing
across something where we don't, uh, expect it, you know, and we wouldn't, we
would only then borrow if it was similar.
And then I actually, I, as a statistician, I struggle.
With only borrowing when it's similar as well.
So I, I do struggle a little bit with the borrowing concept when it's not
underpinned by other justifications.
Yeah, so we did discuss it.
I think ultimately it was because, uh, we are expecting differential
treatment effects here, so we wouldn't.
Scott Berry: Yeah.
Yeah.
The, the problem of dimensionality could.
Be an enemy to you though right now you've got maximums of about 502 groups.
Suppose you added another sub phenotype that made it two by two.
Now 504 different groups becomes 2000.
If you had two by two by two, now you've got, uh, you know,
you, you're making this.
8,000, you're making this an enormous trial.
4,000, an enormous trial without some level of borrowing,
but you're not there yet.
You're two where, and, and borrowing in two is always kind of a weird thing.
Yes or no?
Uh, I, I, I, the, the science of this, do you expect to have more sub
phenotypes in the next few years?
Tony?
Anthony Gordon: Yeah, it is a really interesting point, Scott.
Um, I think there is, there is a strong possibility we
might, um, Victoria might get.
Try and urge just
Scott Berry: Yeah.
Anthony Gordon: to hold back our enthusiasm, but as Danny alluded to right
at the beginning here, the, the, there is this, the clinical, uh, syndromes.
We, we, we talked about a RDS, but there's a massive overlap with sepsis in general.
Um, you know, ar they're like two big parts of a Venn diagram.
They overlap, but actually.
They're very similar, the biological processes.
And so you could imagine we might want to include a broader population with
sepsis and a RDS because the underlying biological processes are similar.
And also the, these hypo and hyper inflammatory phenotypes are
probably the most well described.
But there are others work we've been doing.
Um, with colleagues in Oxford, for instance, uh, Julian Knight, um,
around gene expression profiles that is looking really promising as well as
identifying, um, sub phenotypes that will respond to different treatments if
we were then to bring them all together.
Then I think you're right.
Making a good point of why we might need to consider borrowing, but
I, I don't think we're there yet, but we're always thinking big,
um, and looking to the future.
But I think probably that's where we need to go to take the whole area of critical
care research, um, further forward.
Um, but we, we might need to come and revisit that, um, and
do some brainstorming about what that actually would look like.
I think.
Scott Berry: Mm.
Danny McAuley: And I guess Scott, the other thing to say, you know, we're,
we're saying we've got this heterogeneous mass and we've divided into two, and
the idea that two is the ground truth.
So I think this is just the start of the, the journey to get, you know, better
definition of all of these sub phenotypes.
And that's one of the really important other design features were.
Capturing biological samples within the trial as we go along
to hopefully understand the, the, the syndromes better as well
Scott Berry: So I imagine, suppose Simvastatin enrolls 500
and 500 and it gets to the end.
You've got these
Danny McAuley: and works and and, obviously he's gonna work.
Scott Berry: right.
Yeah.
Well that was clear.
Um, but the, you've got the sub phenotypes, but I imagine you're
gonna do a great deal of after the fact investigation of heterogeneity
treatment effect over all kinds of different, uh, other things when the
data are finally in, uh, also creation of new sub phenotypes based on the
data that's accruing within this trial.
Yeah.
Anthony Gordon: Yeah.
And, and Scott, I think that's an important part.
These, these phenotypes have really emanated from postdoc analysis of a
more standard traditional A versus B.
Trial.
And I think part of the international collaboration here is about
trying to bring those who are interested in this field together.
And this isn't just clinical trial, this is, there's people in the
international group that do much more of the basic science and will do
that biomarker work, that discovery, and actually try and take the whole
field, uh, forward, uh, together.
And so, rather than.
Do it on an ad hoc basis, can we sort of plan it upfront that we are actually
setting up the whole infrastructure, randomized patients in the trial, learn
about those specific questions that are the randomized questions, and at
the same time, um, build that precious resource that, um, is exploratory but
drives the next question that can come into the platform, um, in, in the future.
Scott Berry: Yeah, it makes a ton of sense to have this central resource of data in
a RDS with multiple treatments to do this further, moving the science forward of
understanding a RDS and endpoints and, uh, uh, different phenotypes is, is amazing.
Uh, where if everybody did these trials separately.
E, this is a much weaker.
Global effort in a RDS, which is one of the, the, the things that I don't think
is talked about much, um, is that the, having all this data together, so this,
we, we've talked about the huge advantages of this, this bringing all this data
together, bringing the multiple arms in.
Uh, what are the challenges, uh, uh, in this moving forward?
And I, I assume some of them are operational, logistical.
I, I don't know if they're funding.
What are the challenges that you're going to be facing, uh, maybe
initially in running this trial?
Victoria?
What keeps you up at night, other than having me on your
DSMB, what keeps you up at night?
Victoria Cornelius: I, I definitely wanna bring in to Tony and DNI on this as well,
but just so as you introduced me at the start, I also direct the, the kind of.
Trials unit at Imperial.
And actually for us, this is a really important, uh, platform
'cause it's our first platform.
And, uh, we've got, you know, we've got a lot of trials in our books and
we've got about IET at the moment, but this is our first platform.
And so we've had to learn quite a lot, uh, uh, across the whole team.
Obviously the.
Statistical team.
Um, uh, it is, it's, you know, the funding for that, how to deliver and
work together, all the rest of it.
Our standard operating procedures.
We've got our operational side and also our, our clinical data systems as well.
So it's been, it's been quite a journey for us o on that side of things.
And like I say, uh, we talked about the funder, but actually NHR uh, funded us.
For an accelerator to get ourselves ready.
So we had a year, uh, of preparing, you know, designing that trial.
And then we've had a very generous funding, uh, to get the
platform up and start as well.
So I think we wouldn't have been able to do that now that we're embarking on it.
Um, I'm gonna, I'll, I'll let Danny and Tony come in to what,
what may be worrying them.
Danny McAuley: So I, I mean, I, I guess this is probably a, um,
a global issue to some degree.
But, but, you know, clearly we want to protect patient safety at all costs,
but the actual process and governance process of getting research established
particularly, um, in our experience in the UK is very, very difficult.
So I, I think, uh, that that is the one thing that that keeps.
Well, not one, the one thing, but one of the many things that keeps
me, uh, up at night and in terms of how we actually embed research more
efficiently and, and increase, uh, recruitment into these important trials.
Under just the bureaucracy that we face in, in getting the trials open.
And it's a really important, uh, sort of national priority, I guess.
The, the, the, the one other thing we, we work very closely and we
talked about, um, the device that we, uh, use, uh, to phenotype patients.
That's on a, a collaboration with, uh, a company called Randox and,
uh, getting the, uh, sort of, um.
Devices deployed at sites despite Rand's.
You know, full support has been a, a challenge as well.
And, and scaling that up internationally then, um, presents,
uh, a potential, uh, challenge.
I think, we'll, we'll overcome it, but they would be the, the
two that worry me the most.
Uh, but let's see what Tony has to say.
Anthony Gordon: Yeah.
Um, well now that we are funded, obviously that was the first issue
is getting, getting the money and also particularly getting money
in more than one, uh, region, you know, the international trials.
But we, we, we are making good progress with that.
Um, I think.
Obviously there's elements of this, as alluded to, it involves both the
device to measure the sub phenotype, the, the biomarkers and the drug.
So you've got, you've got both device and drug aspects to manage.
It's large and it's international.
So I, I think the coordination of that by the trial management
team is so crucial and I think.
Uh, it doesn't keep me up at night 'cause I know I've got a good team that do it.
But, um, I just would, I, I think I just need to recognize,
uh, those, uh, team members.
Uh, so in this case our, our team leader, Janice Best Lane, just as phenomenal.
Her and colleagues have, uh, learned through COVID.
They worked, you know, on the, um, in remap Cap and the
challenges there, but how you keep.
The whole, um, ship, um, sailing, um, to manage this,
you and you do need that team.
And so I think, uh, sort of advice to anybody setting out on these sort
of things is you have to have that support team there to manage all
aspects of the protocol that the modular nature of the, um, of that protocol.
We are moving to try and do it all electronically rather than on paper,
for instance, that things like that help, but then to coordinate it and
keep all the sites involved around the world, um, to coordinate when there
are so many things that can change.
I think running any international trial is a challenge, but if it's a
fixed protocol that doesn't change.
It's still a challenge, but if you're gonna change it over
time, how you manage that.
And so, um.
I, I think it can be done, but you need experience.
You need an experience team.
And so I just want to recognize the hard work, uh, they put into to deliver it.
Danny McAuley: I just wanna second that.
I mean, Janice and, uh, the team managing me, Tony and Victoria
in itself is a challenge.
Nevermind the, the, the whole trial infrastructure, but the, the, the
other thing I just wanted to pick up on was that the funder, and it
is this problem that we've had in the past of this idea of going to
multiple jurisdictions and facing.
Double, triple, quadruple jeopardy to get your trial funded.
And I, I think we're starting to see funders work together,
uh, on big ticket items.
So I think hopefully going forward, uh, that might be a, a,
an easier issue to get sort of,
Scott Berry: Hmm.
So there,
there's a potential moving forward that you could bring in a pharma sponsor,
uh, that, that could bring in funding.
Another, uh, a way to bring in funding of this.
What does the trial look like going forward?
You know, what does steady state look like?
What would be the optimal number of arms?
And to some extent, there's a risk that one of these two treatments say drop in
hypo, the other one drops in hyper and you're now running kind of an AB trial
and each, you only have one arm in that.
Would you like to have.
Five arms, two arms.
What is steady state and what, what is moving forward?
What would you like this to look like?
Tony?
Anthony Gordon: Um, so importantly we have a pipeline, and that was something
we set up right from the beginning.
So there are already drugs in the, um, in the queue waiting to come in.
So if, if we are lucky and get an early win.
And that's an answer.
I mean, that if, if we learn it doesn't work, that's still a win.
We, we know it doesn't go forward and then we've got drugs ready to bring in.
So, and importantly I think we have a process by doing that as well.
So, um, and part of that is internal.
We've have a prioritization committee, but we've also got an external committee
to advise us, um, that includes clinical and pharmacology expertise to guide us.
And I think that's something I've learned.
From platforms, how you decide what comes in.
It's good to have that independent oversight.
I think it depends how many sites we have open.
Um, and Victoria alluded to this, if we, we were talking 70 sites initially,
we think the three arms with the two active interventions is probably the
right number to get answers quickly.
But if we manage to open 200 sites, um, because we are able to.
Measure the biomarkers in, you know, more laboratories, for instance, I think we
could then bring in a, you know, a third active intervention at the same time.
Um, it it, so yeah, with that extra resource, we could do
more, but we, we thought sensible to, you know, manage that.
Um, at least initially.
Scott Berry: Mm.
So Tony, suppose you get word back.
Uh, so, sorry, sorry.
Uh, Danny, suppose you get word back that Simvastatin is successful in this trial.
It's promising.
What happens?
Uh, do you run a phase three trial?
Does Panther run a phase three trial?
It's, I, I think this is completely, uh, off patent and generic.
What happens?
Danny McAuley: So I, I guess simvastatin is, um, probably a wee bit different from
maybe some of the other drugs coming in.
And I'll maybe explain, picking up on Tony's point.
You know, there probably is a, a pretty strong prior in the hyper inflammatory
group that, uh, simvastatin might work.
And if we showed in a big phase two.
With, you know, good certain day of, uh, um, positive effect that might be enough
to change practice in that, I think fairly unique situation in most situations.
You know, taking, uh, baricitinib, there is some proof of concept
largely from, uh, COVID, but it's not probably enough to change practice
even in the setting of a positive readout from the, uh, Panther trial.
So to me, in that setting,
that's where we would.
We would feed the beast that is, uh, remap cap, which is so well set up to
answer these multifactorial questions.
And that's other, that's one of the other things that we, you know, talked
about in terms of pandemic preparedness.
You know, one of the nice things about Panther and Remap Cap working
closely together is that, you know, if we did a pivot in pandemic
preparedness, we would be able to.
Quickly prioritize phase two assets that then could go into
the, the, the phase three that that remap cap does, uh, very well.
So that's how we sort of, uh, imagine that would work.
Scott Berry: Mm.
Anthony Gordon: Scott, can I, uh, suggest another alternative as
well, and it's the sort of industry.
Uh, perspective here.
So I think that, you know, what we think is that, um, pharma companies
will have a number of drugs already.
Maybe they're already, um, got licenses for other respiratory
or other inflammatory conditions.
It's a big ask for them to, um, maybe run their own phase 2 trial.
That, you know, we, as we've talked about, the issues with critical
care trials, um, that haven't.
Produced, uh, successful results.
The idea would be we have a platform already up and running their asset that
they have maybe using in a chronic lung disease, put it into the Panther platform.
We've already got the infrastructure there.
We've essentially de-risked it.
They learn whether the drug is looking, promising.
If it is, they get that result and they might choose to do their own
licensing trial, um, for this indication.
Or they learn it wasn't effective, and they learn that, uh, quickly
and we've sort of de-risked the whole process for them.
So we think this would appeal to them and, and gives a better
chance for us to actually, uh, bring new therapies to patients.
And it's that academic industry collaboration that, um, I
think could be really helpful.
Scott Berry: Uh, yeah.
And the amazing thing is for, for that pharma company to go out and run that
phase 2 trial and go get 70 sites and, uh, get devices and all that might, might
cost x million dollars for you guys to do.
It might be a 10th of that.
Uh, and the cost, I, and I don't know what it is, but some fraction of that
to, to do this, to take this shot on goal to, to the benefit of all, maybe
you guys get 10 times as many shots.
Because, because of that, it's just such a, an awesome potential.
It seems by the way, that many of these platforms have come about by
patient organizations in pancreatic cancer, in glioblastoma, in a LS where
not things don't work and companies stop taking shots on goal because
it's so challenging and many of these platforms are developed for Exactly.
Trying to solve this, the, the, this, this dilemma.
It's, it's a huge potential.
Danny McAuley: Y Yeah, no, I think that's right Scott.
And, and as Tony said, the, the idea of de-risking in a high risk.
Environment that is critical care.
You know, and the sort of the, the, almost the taking smart risk, uh, is, is
sort of the mantra that we're trying to sort of get across to, uh, pharma, that
that will be of benefit to, to them, but also to, uh, patient, uh, outcomes.
Scott Berry: Hmm.
And, and, uh, uh, a hugely positive thing with a successful
drug in a RDS that improves.
Organ support free days of the, the, the size of the potential,
uh, win and the, the benefit.
Uh, so the huge potential at the end of the day just been a,
a challenging area to go into.
All right.
Uh, a very cool trial.
I'm, I'm, I'm proud to, to watch this go on and excited to see how this goes.
Uh, and lots of times I will be in the interim and, uh, I appreciate
you all coming here in the interim, uh, and joining us all.
So thank you all.
Victoria Cornelius: Thank you very
much.
Thanks.
Anthony Gordon: Thanks.
It's been brilliant to chat about it, sco.
Cheers.
Scott Berry: Yeah.
Wonderful.
Thank you.
And everybody else, we will be here in the interim.