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: Welcome everybody back to In The Interim.
I'm your host, Scott Berry, and I've got a, a, a wonderful topic today and I was, I
was chatting with Steve just before we hit go here on, th- we're episode, I believe
episode 65 of In The Interim, and I think, uh, at, you know, spending t- I've
been doing clinical trials for 27 years.
If I were to stop tomorrow and somebody said, "Scott, what was
your biggest accomplishment?"
It would be Remap-Cap.
Remap-Cap to me will be, you know, one of the incredible things in
my life, the experience of it.
It in of itself as a scientific beast, the impact it's had, the,
the so many aspects of it, the friendships that have grown out of it.
So it's, it's the most impactful and here we are, episode 65, and this is the
first episode on the Remap-Cap trial.
Part of it is it's such a beast to get your arms around.
So I, I'll introduce and we'll, we'll talk about this.
This is going to be the origins of the Remap-Cap trial.
In and of itself is such a cool story of it, and my guest today
was there, creation of this.
Also a very good friend, uh, uh, of mine, Steve Webb.
Steve is a professor, uh, is intensive care specialist and
a professor of critical care research at Monash University.
He's also the executive director of Empiric, which
is a whole separate podcast.
Uh, interestingly, you know I do a lot of sports things and, and in sports they
talk about a first ballot Hall of Famer.
Steve, in 2014, the Australian government estabuli- established the
Australian Academy of Health and Medical Sciences, and he was part of the 14
fellows that initiated the academy.
So very well-respected researcher.
He's, his clinical trials he's designed have enrolled more than 70,000
patients, 200 million in funding, more than 30 papers in The New England
Journal and JAMA, more than 75,000 references, huge impact on patients.
He's also one of the global leaders of the Remap-Cap platform trial and was
the head of the International Trial Steering Committee when COVID hit, and
that'll be a big part of our story.
So Steve, welcome to In The Interim
Steve Webb: Thank you very much, Scott.
It's a, pleasure to be chatting about The Beast
Scott: Yes, the beast.
All right.
So I was curious going back and, and remembering this, and I got in a bit of
a, of, of a rabbit hole, uh, with this and looking back at all the emails.
I wanna know, when was the first emailâ¦
I have all my emails ever from Berry Consultants, which is, is
fun, fun things going back to.
The first email that ever showed up with Steve Webb on it.
So I look back, and this was, uh, March 13th, 2012, is the first email
where you and I are both on the email, and it's from Derek Angus.
It's a follow-up to a Pittsburgh meeting that is talking
about potential p- pandemic.
Sorry, I wasn't there, but, uh, the aftermath of this came about.
Do you wanna describe this meeting and the subsequent meetings and pandemics?
Steve Webb: So the story of Remap Cap really starts in the southern hemisphere
winter of 2009, when the swine flu pandemic, uh, spread around the world.
to Australia, New Zealand, other parts of the southern hemisphere, uh, first,
and it, it was a decent pandemic.
Um, uh, in the Royal Perth Intensive Care Unit, where I was a, a specialist,
uh, at the peak of the pandemic, half of the intensive care unit
was occupied by patients with swine flu, all of whom were ventilated,
all of whom, uh, were very sick.
Um, but, uh, swine flu, um, came and went, um, uh, uh, over the space, uh, of two
winters, one southern, one, one northern.
And, uh, um, the world sort of, um, took a breath and said, "Well, that was bad,
but it could have been a lot worse."
And so a bunch of people got together from the intensive care world to
think about how could we be better prepared for future pandemics.
Um, in Australia, New Zealand, uh, we did some observational, um, uh, work, which
was, uh, quite valuable from a public health perspective, we had no chance
of putting together a clinical trial in the time span that was available.
A wave would hit, it would last about eight weeks, um, and you just can't launch
trials, um, uh, at least, uh, at that time, over that sort of, uh, timeframe.
was a, a meeting in 2010 in Toronto, uh, where Derek Angus, uh, who was
also, uh, um, one of the, um, together with you, me, and Roger, probably
the midwives, uh, of this thing.
Um, and your dad spoke at it, Scott.
Um,
Scott: Yep.
Yep
Steve Webb: talked about adaptive platform trial methods, and it made a lot of sense.
Although I've got to say, I had to listen to talks from Don, from you,
from Roger, at least six times before I, um, finally thought, "I-- Now
I understand this, uh, this thing called an adaptive platform trial."
Um, and then the 2012 meeting that you referred to was in Pittsburgh,
and Roger, uh, Roger Lewis was there.
Um, and, um, uh, that was really, a series of meetings about, you know, nine
months apart, we decided that adaptive platform trials were the only thing
that made sense for future pandemics.
Because they create, um, um, warm infrastructure can pivot and adapt rapidly
to whatever is needed for a disease that can't be predicted in advance.
Scott: Uh, that, that, that I think comes to fruition.
So there's these d- lots of researchers meeting, ISARIC.
Uh, John Marshall was at a number of these meetings, who ends up
being a, a, a, a very important player in the REMAP-CAP story.
And I, I think myâ¦
I enter this in, uh, on July 2nd, 2012.
There's an ISARIC meeting in Annecy, France.
I believe you were there.
Yeah.
So I believe it's probably the first time we met, uh, in that,
and I presented on adaptive trials, and it was the first sort of what
could this look like in a pandemic.
There was a two-day working group from that, and I think from that largely
grew the pr- grew the PREPARE network
Steve Webb: Co-correct.
Herman Goossens, uh, was a, um, very, um, inspirational and influential infectious
diseases physician based in Belgium.
uh, he understood the damage that pandemics could, uh, do to the world if
one turned up, and the critical need of being able to generate evidence rapidly
about, uh, um, optimal treatment in a situation where, um, the clinical
trial, uh, design and infrastructure needs to be constructed, um, in the
presence of enormous uncertainty.
And so Herman, uh, um, uh, um, uh, proposed, uh, to the European Union
that there would be a funding call for a consortium around pandemic preparedness.
And it was a fantastic program of work.
There was lots of laboratory science.
There was stuff about, uh, diagnostics.
There was stuff about consumer and community engagement, about how you
prepare the community for a future pandemic in terms of the research that
needs to be, uh, conducted at the time.
And one of the work packages, uh, work package five, as I recall,
was an adaptive platform trial, uh, for, um, any future, uh, pandemic
Scott: Uh, yep.
Uh, and, and that's sort of where, where I, I sort of really remember starting
on this, and it was called Prepare.
And we were talking about at the time, I think we were talking
about a platform for antibiotics.
It, it was relatively generic treatment, but we, we hadn't jumped into the,
the, the multifactorial, the huge aspect, which is really interesting
part of the pandemic was the abil- was the factor- multifactorial story
of that, but we'll get to that.
But it
Steve Webb: Yeah, no, I,
think,
Scott: it wasâ¦
Steve Webb: I, I
Scott: Yeah
Steve Webb: I think it, I think it was multifactorial from the get-go.
But part of, um, uh, the discussion and the concept at the time that the only way
to be ready for a, a, a pandemic was to have that were already recruiting to other
questions that were-- that are relevant, uh, to improving patient outcomes.
and so part of the concept was to construct this, uh, platform that
would, uh, do good things, uh, during the inter-pandemic, uh, period.
And, uh, um, patients with pandemic influenza, or as it turned out, pandemic
COVID, have, um, essentially a diagnosis of severe acute respiratory illness
or community-acquired pneumonia.
so the plan was to construct a platform that would recruit patients, uh, with
community-acquired pneumonia, ask questions that were relevant to improving,
uh, patient outcomes, because CAP is a, um, a major driver of, um, um, uh,
bad outcomes, um, and be able to pivot, uh, when a pandemic, uh, turned up.
So having succeeded in getting that grant call, uh, included within, um, what was
then the, uh, FP7 scheme, subsequently has become the Horizon, uh, scheme.
Um, the, um, uh, um, put together a really impressive, uh, uh, consortia.
Um, uh, Derek, myself, you, all contributed to, uh, the design
of what was included within work package fee-- uh, work package five.
it
Scott: And
Steve Webb: uh, I don't know, it was maybe a page and a half
in this, uh, massive grant
Scott: Yeah.
Steve Webb: And, um, uh, after the wheels turned inside the
European Union, e- I can't even remember exactly what year is it.
Might have been 2015 or 2016 now.
grant is, uh, successful, and we're away
Scott: Yeah, and interestingly, as part of this story, the federation of this,
this trial grows into something that has multiple sponsors globally and a single,
uh, platform that, that has the federated, and we, we talk a little bit about that.
But I found an email in December of 2013 where you send out that you
now have funding from the NHMRC, uh, to extend this to Australia
and, and what this would look like.
And this starts a little bit the federation of what becomes Remap-Cap
Steve Webb: Yeah.
So that money was largely used to, um, uh, pay for the preliminary work
that was necessary to write a grant application to the NHMRC, uh, for what
was called various things back then.
Uh, it was-- Once upon a time, it was GACSARI, then it was ADCAP,
and, uh, then it was OPTIMIZE-CAP.
but that NHMRC grant application, uh, uh, was, was successful.
And the preceding FP7 grant, I think, made a massive difference to the likelihood of
success of the Australian grant because it had already been through peer review
in another location, though it was a relatively small part of this big, massive
pandemic, uh, preparedness consortia.
But that gave it credibility, and I think that likely helped,
uh, get it over the line.
So that had us funded in two countries, in, in two regions.
And
next to come on board was John Marshall, who somewhere through that time period
was successful at getting, uh, it funded, uh, through the CIHR in Canada.
And, um, really with Derek's intercession, um, we settled
on the name of, uh, REMAP-CAP.
Uh, uh, De-Derek had had a, um, uh, a viewpoint article in JAMA through
that area-- through that era, he had, um, proposed the term REMAP
to describe, uh, you know, the, the generic description of the beast.
A randomized embedded
adaptive, uh, platform trial.
And of course, it was also remapping the way that clinical trial evidence,
uh, should be, uh, should be generated.
Uh, uh, Derek's, uh, uh, well, he's, he's got-- Uh, uh,
Scott: Yeah.
Steve Webb: Derek's, Derek's not short of marketing ability,
and it matches his substance.
Scott: Yeah, yeah, and a, and a fabulous name.
So a little bit, you touched on this a little bit.
Let's, let's talk about the sort of scientific structure of this thing
that was created, which started enrolling patients, I believe, in 2015.
The first patient was enrolled in this.
Uh, uh, so it was '15 or '16, it was relatively early.
Uh, it-- we, we weren't, we didn't have a super mature protocol, and we'll get into
the, the development of what I think is a Tolkien-esque document in and of itself.
But the Prepare solution, you talked about this, was to start a standing
master protocol where in the back, in the backdrop to this, we called
it a sleeping strata, we would talk about a potential pandemic.
So if there was a swine flu, if there was Pandemic X, we
could immediately pivot to that.
But meanwhile, there's a t- a trial going on, and I believe the first,
the first therapies being w- used were five different antibiotics
as an antibiotic strategy, so a patient could be randomized to that.
A question of extending macrolide to four days or 10 days, so that was a
second question that a patient could be randomized at in a factorial way, as
long as the antibiotic had macrolide.
Uh, and then was this strange beast, hydrocortisone, um, uh, which I, I'm so
fascinated by corticosteroids and do they work, do they not work, uh, question.
But, uh, patient-- the question was should you give patients steroids,
uh, uh, severe patients, uh, in these?
Originally, I believe this was somewhat severe patients.
This was ICU-based severe patients, and these were the three questions that
were enrolling at the launch of this Prepare trial that migrated in name
to Remap-Cap in a factorial experiment
Steve Webb: There was an initial protocol, um, which, um, to the
best of my recollection, uh, did get us, uh, recruiting in a small
number of locations that didn't include Australia at that stage.
But I think it was apparent that, um, the protocol that had been written
initially was, um, um, w-was a standalone master protocol containing everything.
uh, if one looked as to how this is going to evolve, adapt, new questions coming
in, um, there was a feeling that this sort of, um, single protocol document wasn't
going to be, uh, effective over time.
And that led us to the development of the modular protocol, which, uh, we've used,
I think, quite successfully ever since.
And the principle here is to have a core or master protocol that contains
the eligibility criteria at platform level and the primary endpoint that's
going to be used at platform level across, uh, all of, uh, the domains.
Little bit about the disease of interest in terms of background.
Quite a bit about the statistical methods that are going to be used
in the platform, there's a separate statistical analysis appendix.
But nothing about the, uh, interventions that are going to be
evaluated, uh, within the platform.
So we had to invent a word.
We invented the word domain to describe sets of mutually exclusive,
uh, interventions that would be, um, uh, represent the, um,
comparisons that, uh, existed, around specific, uh, um, modes of therapy.
And the protocol has this structure of a master protocol onto which are
bolted, multiple domain-specific appendices, and they contain the
information about, uh, the background information about why that's a relevant
question and the, uh, appropriateness of the interventions and what's known.
domain-specific eligibility, uh, criteria, appropriate, domain-specific secondary
endpoints, my favorite section of every REMAP-CAP protocol, the statistical, uh,
approach to this particular domain, which is like selecting from a menu that is
set out in the master protocol, in the core protocol, about what statistical
triggers, what combination of states and strata apply to, uh, the, to this domain.
Um, so, um, uh, that modular protocol structure I think has been a critically
important part of the success of REMAP-CAP, it was a substantial advance,
and it proved its worth in the pandemic, where with this modular structure,
could write a new domain-specific appendix, do the associated data
management changes, and have a new domain running in three or four weeks
Scott: Yeah, I'm, yeah, so, uh, it, we- we'll get to the pandemic, but
I agree with you that the previous document wasn't ready for that.
And I remember we had this sequence, there were a number of players involved.
Colin McArthur was involved, Alastair w- was involved.
But it was a sequence of about a, a three weeks to a month
where you, Derek, and I wereâ¦
It was morning in the US, it was your evening.
Derek and I would have coffee, and you would have a glass of wine next
to you, and we'd be working on it.
The- then all of a sudden, you'd wake up the next morning, and it would be night,
and Derek has a nice big, uh, glass of wine, and you've got your coffee.
And it was morning and night, and morning and night writing this.
And I refer to it almost as Tolkien-esque because Tolkien, when
he wrote The Lord of the Rings and all this, he invented languages for
the Elvish, he invented songs, and we had to invent all this terminology.
What, what works for this description of a common set of
interventions being compared?
And you can't reuse a word that means something else in clinical trials because
then everybody confuses what you're doing.
And we spent a huge amount of this inventing terminology that allowed this
modular thing, that you had to build this entire protocol infrastructure so that
you could plug in a DSA and remove it, and the protocol doesn't change at all.
I, I mean, it's built that you plug it and pull it out, and it functions, and
as you say, incredibly quickly we're ans- we're, we're addressing that question.
Uh, it's part of the database.
And so the, the master protocol itself is this amazing thing that has
come out of Remap-Cap that, by the way, many people have used, copied,
which is fantastic, modeled after.
It in and of itself is an incredible sort of scientific achieve- achievement
Steve Webb: Um, and, um, uh, I've spent a lot of time in the last couple of
years, talking to clinicians or even clinical trialists who've got experience
with conventional clinical trial designs about adaptive platform trials, and
it's the concept of the domain, which is one of the most difficult concepts
to try and articulate and explain in a way that, uh, people get it.
But I've got a new technique which is working really well, which is that I
tell them, if the goal of the platform trial is to try and design the best
possible Big Mac, then what you have is the components of the Big Mac as domains.
So there's a pickle domain, yes or no for pickles.
There's a beef patty domain.
Do- is it flame grilled or fried?
Um, and, uh, people suddenly get the idea of what a domain is.
But we had to go to a Big Mac to make progress.
Scott: And we then had to name the Big Mac is when you get all of the pieces of the
domain that work, what do we call that?
And we called that a regimen.
So each piece together, the Big Mac itself is another regimen.
We, we have patient subgroups where there may be differential
effect, and so we named this and named all these pieces to it.
S- so we went through this amazing thing.
We set up the statistics.
We, we talked about it.
We set up response adaptive randomization can be done within the trial.
We set up the entire thing as Bayesian.
Uh, and interestingly, a foreshadowing of, of medical papers that come
out of this have zero P values.
All Bayesian triggers in all of this.
So this is kind of all set up, and as you d-- as you, as you've said, when
we had meetings maybe two thousand seventeen, everybody would come together.
We've got this new protocol, um, uh, in this Genevieve O'Neill, who's
not working on Remap CAP anymore.
She was on every one of these calls, I think, in, in making
this go forward from Australia.
But that we had more investigators than patients at the time.
Uh, we're enrolling CAP, and then
Steve Webb: there, there, there, there was celebrations, there were fireworks,
uh, there was champagne popping when we finally had more patients
enrolled than we had investigators
Scott: Yeah.
And by the way, we still, uh, after the pandemic's over, we're
back to this question of CAP.
These patients are absolutely informing conclusions, and we've
got exciting conclusions within CAP.
But meanwhile, um, a, a-- this Wuhan disease comes up, and it was interesting
looking back at the, the genesis of this from early 2020 in January.
There's this weird thing going on until March when it became part of REMAP-CAP
Steve Webb: So one of my favorite emails from, uh, Remap, uh, Scott,
is the one I sent to, um, Green, who is the extraordinary, amazing
project manager that, um, uh, carried Remap CAP through the pandemic.
Uh, Cameron sends me, um, news links to this new disease in Wuhan, and he
copies, uh, it to Colin MacArthur, and, uh, Cameron says, uh, "Do you think,
uh, we need to be, uh, worried about what's happening in, uh, in, in Wuhan?"
Um, and, um, uh, my response to Cam is, "Oh, you know, Cam, in the last
couple of years there have been these sort of little mini outbreaks.
They, um, uh, cause a little bit of excitement and then they, uh,
disappear, uh, reasonably quickly.
That's what I expect will happen, uh, to this one.
besides, um, no pandemic in 2020 please.
We're close but we're not ready."
Scott: Yes, yes.
I, I, amazingly, we've said many times, "Oh, we would've been so
much better off if it was COVID, uh, 20, uh, or one year later."
Now, we were never gonna be ready for what it was, uh, and it was going to be around
the clock, but, but it was, uh, it wasâ¦
I- Iâ¦
And then it hit.
And one of my other favorite emails was, uh, right about that time, we were now
starting to get ready to run this trial.
We had enrolled a set of patients.
We were talking about doing analyses.
Um, and I think we had done several analyses up until this point.
So I brought on two statisticians to help me, uh, Lindsey Berry and
Elizabeth Lorenzi, Liz Lorenzi.
And, um, they have this email of saying, "Yeah, we've got
this little thing in Wuhan, but, you know, don't worry about it.
Um, uh, it's not a big deal."
And they look back at this, and now they've, they've been heroic in
the, the analyses that have happened within Remap Cap as well, and this
has now become, uh, uh, an amazing story of their involvement as well.
Okay, there's an i-
Steve Webb: don't know what-- I, I don't know how much you want to talk about the
pandemic, but, um, I think it's worth just w- at least one anecdote, uh, Scott.
The, the speed with which the platform was able to do things was extraordinary.
We talked about being able to launch a new domain in three or four weeks.
although there were times during the pandemic when even that felt too slow.
But
Scott: Yeah.
Yeah
Steve Webb: able to launch a new trial for, for, um, a condition that's never
existed for, um, interventions, for new set of interventions in three or four
weeks was, was, um, uh, was unprecedented.
But, um, we had this result in November of 2020
Scott: no, let's hang on.
Let's not, l- let, let's sort of set this up a little bit.
I do wanna shift completely to the pandemic now, so let,
let's talk about the pandemic.
Let's talk about the, the start of it, and I've got an email from you, you're the
chair of the ITSC, where you met with, uh, uh, groups, uh, monitoring the pandemic.
There are patients starting to trickle in at sites where Remap-Cap
is a trial there, and I've got it on March 2nd, 2020, that you declare,
"We are open for the pandemic,"
Steve Webb: We had
Scott: at this time
Steve Webb: we had a sleeping strata was in the first version of the
modular protocol, and the question to the ITSC was should we activate,
uh, this, uh, sleeping, uh, strata?
there was a, um, a unanimity within the ITSC that that was
exactly what we needed to do
Scott: So now this trial that had been built, been, as you described, all the way
back in 2009, uh, I'm, I'm sure pandemic preparedness has gone back further than
that, but this whole idea of a platform trial being generated from that, getting
funded by the EU, moving on to the different Australia thing, this idea,
all of a sudden, March 2nd, 2020, the trial is now enrolling in the pandemic.
So we've avoided this whole issue of, okay, now we have to
design a trial for this question.
We're already enrolling.
By the way, we have patients coming into this.
And so the things that were already in the trial, some of
these shift over into COVID.
Uh, all three of them shift over.
I think antibiotics became a not very interesting question within them, but
macrolides became very interesting.
Steroids became s- s- very interesting.
Now, this is the part that you sort of touched on, is now the
ability within the modular approach to start to add questions to it.
So now we're open for business.
We already have therapies we're, we're, we're interested in, we're shifted.
Now, what does this process look like?
Steve Webb: So the ITSC establishes, um, processes to consider what interventions
we evaluate in this, uh, new disease.
We're learning about this news-- new disease in a very, uh, ad hoc way.
um, um, uh, uh, my recollection, um, quite a bit in the p- in the,
in the general media about all of these patients ending up in ICUs on
ventilators, of, um, arterial and venous thromboembolic, uh, complications.
There's actually relatively little published, even in terms of, um, uh, case
reports and, uh, cohort, uh, studies.
Um, uh, a-and so we have to start making decisions about
what's going to be evaluated.
Um, we have an existing corticosteroid do-domain, which
includes, uh, hydrocortisone.
We make some modifications to that domain, including, um, a d- a
different dose of, uh, hydrocortisone.
And we actually managed to recruit the first COVID patient into a COVID-specific
domain for corticosteroids, I think on March the 6th, which is before the
WHO officially declared a pandemic.
So that I think reflects the, uh, the flexibility that the adaptive platform
trial provided in this, uh, scenario.
But we think about what else should be evaluated, relatively
quickly, we put together domains to evaluate, um, uh, drugs which are
thought to have antiviral activity against the, the SARS-CoV-2 virus.
Um, there's a domain proposed, uh, that, uh, comprises, uh,
different immune modulators.
interleukin-6 receptor antagonists like tocilizumab, uh, anakinra, uh, interferon.
there's also a question of whether or not patients should be routinely
therapeutically anticoagulated, uh, with heparin, and that had, um, um,
entered practice just seen as being, um, appropriate to prevent arterial and venous
thromboembolism, given the high incidence that was, uh, was being observed.
Sorry.
Excuse me.
Um, um, uh, there's
also
Scott: so let's
Steve Webb: of
Scott: let's set time to this.
I believe, so March 2nd, uh, uh, REMAP-CAP says we're now enrolling patients
COVID, suspected or proven COVID.
March 6th, four days later, you're randomizing to something that
was already there, the steroids.
Added the, uh, immune modulation domain before the end of March.
The convalescent plasma domain, I think, was added in April.
Anticoagulation, as you described, is early May, uh, within that.
So I believe this, this idea that you said every couple weeks we're adding
them, and to some extent that felt slow, but we're doing this and adding
those, uh, before just as May starts, we've added all these particular
questions in a multifactorial thing.
So some patients are being randomized to four and five
questions at this point, which is
Steve Webb: Y-y-yes, I think that,
Scott: just, amazing
Steve Webb: I think at the height of the pandemic, um, um, the,
the, the largest number of, um, interventions that were assigned to
a patient in Remap-Cap was seven.
Scott: Mm-hmm.
Mm-hmm.
Steve Webb: that's m-m-that's multi-multi-factorial
Scott: Yeah.
Yes, yes.
Okay, so now it's we're, we're, we're, we're getting set up.
And meanwhile, uh, as you describe, it would've been nice
had this been another year.
We're getting the operational part of this.
We have multiple databases that are contributing to this.
We want to be doing interim analyses very frequently in this trial.
So it is a great deal of work by a, a, a huge number of people to get
this ready to start doing analyses.
And then mid-June happens.
Yep
Steve Webb: many, many, many people literally working 14, 16-hour days,
seven days a week across many countries.
Um,
Scott: ãã
Steve Webb: Green, um, Colin, uh, the, the, uh, Lisa Higgins, who was
putting the data together at Monash at that stage, the teams at Berry
Scott: Yep.
Yep.
Uh, the UK enrolling patients, Tony Gordon, Lenny Deirdre,
Steve Webb: Yes
Scott: all of this, uh, amazing.
So mid-June happens where, uh, we've done interim analyses, but
nothing is triggered at this point.
We've got triggers set up.
Mid-June, the RECOVERY trial, which by the way, in and of itself is an
amazing story of the RECOVERY trial.
We're-- REMAP-CAP's largely enrolling severe.
Meanwhile, we, during I think July, we open what's called a moderate
state, uh, a step different.
So we're adding to the patient population in a modular way as well,
but we're enrolling only severe at this point, defined as being on
intensive care-based organ support.
Uh, and we went through a whole bunch of things at this point is what is
the definition of an ICU, uh, because people are using non-ICU things, and
we, we had to lose the notion of what, whether you're located in an ICU or
do you have I- uh, ICU-level care.
So there were things we had to redefine because of the surges and all of that.
But the RECOVERY trial comes out with an announcement based
largely on moderate patients that steroids are, uh, saving lives.
And so REMAP-CAP is enrolling steroids largely in a severe population.
So REMAP-CAP does what at this point?
Steve Webb: Um, so I just want to, uh, uh, comment about, uh,
Scott: Yep
Steve Webb: amazing trial Recovery was.
It was put together incredibly, uh, quickly.
It, it was in some ways also an offshoot of the same group of people
who'd been working on, um, um, uh, Prepare, uh, with, with, with Herman,
uh, Herman Goosens, and as you said, was predominantly focusing on, um,
uh, ward patients, whereas Remap-Cap was exclusively, at least initially,
uh, uh, critically ill patients.
So, as soon as the Recovery result, uh, um, uh, comes out, the, um,
corticosteroid component of Remap-Cap, uh, in patients with COVID, um, uh,
ceases recruitment, and we start this huge amount of work to try and
get, uh, our results, um, analyzed.
Um, only really-- O-one thing that all clinical trialists, um, um, intuitively,
um, know deep in their bones um, there is nothing better when your trial has, um,
uh, reached a certain conclusion, another trial reach the same, uh, conclusion.
Your anxiety levels drop, uh, um, uh, enormously.
Um, so, um, the WHO put together a process to try and do an individual
patient meta-analysis across five or six trials that had been, uh,
recruiting patients, uh, to steroids.
And, um, that all happened, uh, at light speed.
Um, the Recovery result, um, was, um, uh, released, um, uh, changed global
practice instantly, um, in June.
there was a, a manuscript, I think, um, I'm not sure precisely when it was
through, uh, July or August, and but it was September when, um, the WHO,
um, IPDMA was published together with the primary manuscript of these other
steroid trials, including Remap-Cap.
And, um, uh, the Remap-Cap results were strongly supportive of the result
that had come from, uh, Recovery, uh, with five or six hundred patients.
Uh, my recollection, we were sitting on a, uh, uh, posterior
probability of ninety-three percent, uh, superiority for hydrocortisone
over, uh, no hydrocortisone.
we wouldn't have been too far away from, uh, triggering with some,
uh, additional recruitment, but it provided strong supportive evidence of
the benefit of this cheap, available treatment for this dreadful disease.
Scott: Um, uh, it was another really neat thing of the Bayesian
approach that at that time we stopped because care had changed.
We couldn't give a control anymore.
And so we got to read this out, and it was this 93% probability of superiority.
It wasn't that we're non-significant, it was the, the-- in the paper, we
didn't need adjectives, moderate.
It was there's a 93% probability this is beneficial, uh, which was such a
cool part and a simple thing and such a straightforward scientific thing
about a clinical trial that was, was a positive of the Bayesian thing.
Steve Webb: We, we, uh, Scott,
Scott: Now,
Steve Webb: two
Scott: yeah
Steve Webb: we, we need, we need two T-shirts.
One is, "This is a p-value-free zone," and the other is,
Scott: Yes
Steve Webb: treatment, we estimate treatment effect."
Scott: Yes.
Oh, I thought you were gonna go to the T-shirt that you wore much of 2020,
um, that I, I will always remember.
Uh, it had a picture, it was emoticon-based.
It had a picture of a magnet and then a pile of, uh, shit next to
it, uh, which was, which was quite apropos for what was going on, yes.
Um, okay.
So at that time then, Remap Cap adds the moderate state.
It, um, it's now triggering a number of conclusions, uh, and we'll get to
some really important ones of those.
But it's also, um, cooperating with other platform trials in a
multi-platform randomized trial.
So it's working with Operation Warp Speed, um, and the trials, it's working
with a Canadian one where we all pool our data together to have a single
conclusion and, and a result, and we create a new thing for a trial.
Uh, and then we open up a new domain, simvastatin is a- open,
antiplatelet domain is opened.
Um, and then we start coming in with really interesting conclusions
at the end of 2020 into early 2021
Steve Webb: Yeah.
So, uh, um, one of those triggered on Christmas Eve, Scott, and
Scott: Yep
Steve Webb: of us worked all the way through Christmas Day, doing
the things that were necessary.
I thi- I, I, I, Iâ¦
That was one of the anticoagulation results, but I can't remember,
uh, which one it was that, uh, triggered on, uh, December 24
Scott: one was the, um, uh, likely harm of severe.
Steve Webb: Yep.
Yep.
Scott: yep, yep
Steve Webb: But before, but before that we'd had, um, again, a f- a,
a, a c- a, a flurry of activity in about mid-November we'd triggered
for the, um, superiority of, uh, uh, tocilizumab, an interleukin-6 receptor
antagonist, compared to, uh, control.
And I think the timeline is something like as follows.
A week after, or it might have been, uh, 10 days after the statistical
trigger, the then British Prime Minister, Boris Johnson, announces
this result, uh, in a press release, uh, or in, in a press conference.
Um, the following day, the treatment becomes standard care
throughout the National Health Service, uh, in the United Kingdom.
Uh, it's, it's, it's mid-November.
Well, no, uh, uh, sorry, it's late, late November.
We got thatâ¦
I don't know what date we got that manuscript to the New
England Journal of Medicine.
Uh, it, it-- I don't know if it was in December or January, but it
was published in early February.
We're talking about eight or nine weeks from statistical trigger to manuscript
that's been through peer review, it's had revisions done, and it's published.
Uh, uh, it, it, the, it is, it is light speed in the world of clinical trials
Scott: Yeah, uh, a- and likely saved tens of thousands of lives.
Uh, uh, incredible therapy, uh, in it.
It, it, it's amazing now the spreadâ¦
Oh, so t- touching on, so tocilizumab comes out, um, within that.
The anticoagulation being harmful in severe, beneficial
in moderate, uh, comes out.
Common therapies given, very impactful within this.
The-- what's interesting, something you said, and I remember the, uh, uh, not a
panic, but we triggered the tocilizumab result of superiority, and we had had
a surge in the UK of patients, and so we had a good, solid result, but
there were like half, uh, half the patients weren't even to 28 days yet.
And so we triggered this, and the whole f- "What's gonna happen
when all of these came in?"
And of course, it came in almost the same.
Uh, incredibly beneficial is one of this, you know, what's gonna happen.
You touched on this.
I think every result that REMAP-CAP came up with, with its adaptive
design, its Bayesian, its RAR, its, uh, its multifactorial, was backed
up by a result in a different trial.
Typically after that, I think all of these results bore out w- with it, whether it
was antivirals being harmful for severe patients, uh, h- hydroxychloroquine
within this, the benefit of steroids within it, the benefits of the IL-6
receptor antagonist, the anticoagulation result was backed up, the ACEs and ARBs.
Largely all of these things, vitamin C largely doesn't seem to be a benefit.
I mean, it was amazing how it kinda got it right.
You know, and I don't, I don't mean to say in a doubting way, but oh my
God, it kinda got everything right
Steve Webb: Well, um, in, in two and a half to three years, the platform
evaluated, fully tested repurposed medicines for a disease that, um, um,
had never existed, uh, uh, before.
There, there are a couple of results.
I don't think the anticoagulation in critically ill patients was ever, um,
uh, reproduced, uh, by another trial.
I don't think there were other trials, or if there, if there were, they
were, um, uh, um, had insufficient sample size to a-address the question.
Um, one
Scott: the multi-platform.
It was, it was the Canadian attack trial and, and, yeah, the combining together.
Right, right.
Yep.
Steve Webb: the, um, uh, contributions from ACTA4 and,
Scott: Yep
Steve Webb: a-and, and uh, uh, CAP.
Attack, sorry.
Um, but, um, um, um, uh, Recovery reported their antiplatelet, uh,
question, um, my recollection is before we, uh, reported, uh, ours.
And they stopped having recruited about 15,000, uh, patients, uh, which is a,
you know, extraordinary, uh, sample size.
And, um, their results were, um, um, no difference in outcome with 28-day
mortality as, uh, the primary endpoint.
we had this interesting result in, uh, Remap-Cap, which is a rabbit
hole that we shouldn't go down, of po-possibly there being non-proportional
treatment effect across the ordinal scale, uh, that we were using.
But my recollection is that there was something like a 93% or 95% probability
of s- of superiority for aspirin with 90-day mortality, uh, as the endpoint.
if we looked at the recovery survival curves, the Kaplan-Meier
curves, were really only starting to separate around, uh, uh, day 30.
So it's interesting how choice of endpoints and the meaningfulness
of endpoints, um, can impact on the appropriate, uh, or the
generation of evidence to, um, be applied to improve patient care
Scott: Yeah.
Uh, another, uh, sort of amazing thing in the trial and, um, with these 17 results
in COVID that you talked about is they largely, most of them had the same design.
That we're going to enroll till there's a 99% probability of
superiority or a 95% probability that the effect was moderate at best.
Fu- we, futility, that it, it didn't achieve above a certain threshold.
And well, many times we don't have a maximum sample size.
We just go till one of those results are hit.
And we had sample sizes of these largely with these 17 different
things, different designs.
We had sample sizes for the arms from about 100, and a good
number of them at 100, 200, 300, all the way up to over 1,000.
And the time at which it triggered and said, "Here's the answer," varied from,
uh, 100 patients to 1,000 patients all spread out, and it just depending
on the effect of when it happened.
This incredible demonstration of the power of adaptive learning and
adaple- adaptive sample size when time was so incredibly critical
Steve Webb: Yep.
Yep.
Um, um, uh, um, the, the number of patients dying from COVID in any one
week meant that, um, a week's difference in when a result became available
was important, uh, to public health.
Um, one of the things which, um, uh, I, I love about the Bayesian approach
is, is, is just this opportunity set a statistical, uh, trigger of the
amount of confidence, uh, the amount of credibility that is necessary
to, um, conclude a question and then keep recruiting, frequently so that
as soon as there's sufficient, uh, credibility to the result, um, the
experiment, uh, uh, can be concluded.
and I think if, um, I think about all of the things I learnt, uh, when I was doing,
uh, biostats and epi as a master's student
and thought all of these things about, um, um, uh, not answering the
question until you've, uh, recruited your, uh, your proposed sample size
based off a, um, a power calculation.
And I thought, "Oh, these are really, really important,
uh, features of, uh, design."
Um, I, I, I now understandâ¦
I, I still understand why they're important, but I do
think there's a better way
Scott: Mm-hmm.
Steve Webb: Um,
Scott: Fantastic.
And so
Steve Webb: uh, uh, when it's appreciated so frequently the, um, uh, estimates
about the size of treatment or effect necessary to run clinical trials using
that approach are, um, guesses that are capable of being just wrong in a
quantifiable way, wrong in the direction of the treatment effect as well.
And one of the really good things that came out of REMAP-CAP was, we tested
a variety of treatments because they were being used, uh, off-label where
the treatment turned out to be harmful.
And the way
REMAP-CAP statistical triggers are set up, particularly futility, if there's
an intervention that's very harmful, it triggers very quickly for harm.
It's not necessary to statistically prove if that's, uh, um, a valid
concept that something is harmful.
You just need to know it's not effective.
Some of the
biggest public health impact in REMAP-CAP came from early identification
of harmful interventions that were in standard care at the time.
Scott: Yeah.
Yeah.
Incredible.
So the, the story continues.
The REMAP-CAP story continues.
Um, w- it is still, it is still enrolling patients.
I think I looked today, there are 240 sites enrolling.
It's enrolling community-acquired pneumonia.
It's evolving.
It is ready for a pandemic, uh, onto virus or, or, or whatever happens to be next.
We are ready, uh, within this.
We also are getting results in community-acquired pneumonia, influenza.
Uh, we're hoping to have on this show, uh, to, to talk about some of the results
that are coming out, I think June 10th in, uh, Belfast, there are results coming out,
so it is still doing incredible things.
Steve Webb: Um, uh,
Scott: s- yeah
Steve Webb: it just, it, it, it just rolls on
Scott: Yeah.
So in-incredible.
I, I appreciate you helping me start to get our hands around this beast.
The, the beginning of this, the, the-- There's a lot to talk about in this,
and I think we're gonna come back with lessons learned, different results,
specific statistical things, response adaptive randomization results.
So lots more to talk about Remap CAP.
Steve, thank you very much for joining me on the origins of Remap CAP
Steve Webb: Thank you,
Scott: And
Steve Webb: uh, great to chat
Scott: And everybody else, thank you all for listening, and until next
time, we'll be here in the interim