ICECAP: The Adaptive Design

0:00Judith: 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: All right. Welcome everybody back to In the Interim. Today, we are going to talk about, uh, a really cool trial. Uh, and, and I, uh... By the way, I'm your host, Scott Berry, and I have a guest today, and I'll introduce the guest as I introduce the topic.

0:32The topic today is the ICECAP trial, and ICECAP is, you know, if I, if I put together of, of doing this for 25 years, sort of my, my five favorite, three favorite, 10 favorite, whatever, ICECAP is on there. This is a, a very, very cool trial. It's a... I, I think the trial design, the scenario, very cool. And we're gonna talk about that trial design. And, uh, joining me to talk about that trial de- de- design is Will Moyer. Will is a professor of emergency medicine and professor of neurology at the University of Michigan.

1:12He's also a medical and scienti- uh, statistical scientist here at Berry Consultants. So Will, welcome to In the Interim. Will Meurer: Yeah, I'm so, uh, happy to be here. Scott: And, uh, uh, sometimes I ask my guests, "Are you a Bayesian?" And if, if you have video access to this, there are some people that have only audio access to this, I don't need to ask that question as, as Will is wearing a T-shirt with Bayes' theorem on it. So he is declaring his allegiances just from the start.

1:46And ICECAP is a Bayesian trial. Uh, the final analysis is Bayesian. The trial is Bayesian. But let's, let's get to the ICECAP trial. The, the story of the design of this trial is as fun as the design itself. So let's talk about, uh, uh, we'll, we'll talk about the development of the trial. But to give people a sense, what, what is the ICECAP trial? What is the, the syndrome? The, what are we treating in ICECAP? Will Meurer: Yeah. So, you know, when we take like high school or middle school health class, we know that, you know, if your brain stops getting oxygen, um, bad things happen to it.

2:29Somet-- You know, people are lear-- you know, maybe learn, gosh, in, in three, four minutes, your brain is gonna be damaged irreversibly." Um, so when people have problems with their heart such that their heart suddenly stops beating, like they're having a heart attack, there's a blocked artery, or for whatever reason, the electrical information in the heart just goes haywire, um, all of a sudden there's no blood flowing up to the, up to the brain.

2:53You know, the body goes down um, hopefully there's somebody nearby if that happens to you so that they can start CPR and potentially get An automa-- you know, an automated external defibrillator and restart the heart as, as quickly as possible. Um, when I was a medical student at the Cincinnati VA, I was just by the ER one night, um, and, and literally a guy, um, went into cardiac arrest just as we were walking by. And somebody got the, the old school paddles, went up to the guy and, and zapped him, and he just...

3:24He woke up, screamed, like, like... And he, he, he, he-- We got to him before he developed any brain damage. But in, in lots of cases, um, we don't get the heart restarted that quickly, and because of that loss of blood flow, the brain is, is damaged. And, we don't know, though, at the moment that people get the heart restarted how damaged that brain is gonna be. All the cells that are inside the brain, you know, we think of neurons, there's blood vessel cells, there's connective cells there.

3:57These are all hurt by this, this lack of oxygen, but they're not all necessarily gonna die. the idea of treating cardiac arrest, you know, first you have to deal with the heart. If you don't get the heart restarted, you, you know, it, it's very hard to, to live. It's, it's really sort of game over. But if you get the heart, heart restarted, then the most common way people die is because of brain injury, so that they don't wake up. So one of the things that we know is that when the brain is injured, um, temperatures like fevers really harmful.

4:35So the, you know, the way I think about this is there's a bunch of these neurons and other, you know, other cells inside the brain. They've been hurt. They're still functioning, but they're, they're, they're maybe not happy about it. They haven't decided, like, should I, should I turn myself off? Should I go to the-- you know, hit the self-destruct button because the situation is bad and I'm, I'm not gonna be able to recover? Or should I give this a little more time?"

4:59Um, one way of thinking of this, it's, you know, it's an oversimplification of biology, is that when the temperature goes up, more of those cells decide, you know, they're done, that they can't survive this. And we see this not just in, in the brain injury from cardiac arrest, um, but we also see this after stroke, traumatic brain injury. Anytime there's a serious hit to the brain, is, um, you know, this really common situation that fever is bad.

5:30And these are sick patients in the intensive care unit. They're on mechanical ventilators, so there's plastic and, you know, coming out of all sorts of body orifices. So the- they're very-- people are very prone to infection in this fragile state, so these, these fevers can be quite bad. so in the early two thousands, um, well, even before that, like way back... Scott: let's back up a little. So these are patients suffer A cardiac arrest. There are other, there are other reasons why somebody has lack of blood flow, and so the whole therapy that we're gonna investigate might be interesting in there.

6:03But in this trial, we're looking at they suffer cardiac arrest. For some period of time, there wasn't blood flow. It gets restored, so these are patients that have been restored. They come into the emergency room where Dr. Moyer is, uh, in that. And, and then the question is, what do you do? Uh, do we have therapies for them? Is that right? Did I get that right? Will Meurer: Yeah. No, Scott: Okay. Will Meurer: that's right. Scott: Okay. Will Meurer: and this is like a, a...

6:30This is damage to the whole brain. So if you've-- You know, a lot of people are familiar with stroke and stroke research. In there, i-in stroke, you have damage to one part of the Scott: Yeah. Will Meurer: that case, people usually are awake, and you can measure how big a stroke they have by how, you know, how weak their arm is. You know, this is part of, you know, what I do in my, in my daily work, or at least, you know, a few times a, a month when I work on the stroke team.

6:57So stroke, you can kinda quantify the severity with this, you know, with like an NIH Stroke Scale exam. You can do a special type of imaging test, which, which, which you, you've all worked on, a CT perfusion that can say, "Look, this, this is the volume of the brain that's at risk." Whereas in cardiac arrest, we don't have a m- we don't have a real true marker of the severity. It's like the person looks comatose. They're not responding. Maybe they're looking around a little bit, but they're not able to follow commands.

7:25But we don't have a sense as to how big a hit their brain took and whether or not they can, can recover. Um, so that's why we wanna try to implement therapies that, that protect the brain or, or can, you know, limit the damage, um, you know, that would be what can help, help improve the outcomes. So that's, you know, that's sort of the stage. You know, the patient has been resuscitated by usually the paramedics in the field. Um, sometimes a bystander brings it, like an AED, and they g- they get the heart restarted.

7:58And then they're- they've come to the emergency department. And unlike that guy at the Cincinnati VA who woke up screaming that his chest hurt, these folks are, you know, on a mechanical ventilator, you know, and really, you know, not, not able to speak or, or follow commands. And that would be, be the coma after cardiac arrest that is, is the brain injury. Scott: Okay. And, and the heat you described that could accelerate neuron death and it considered to be a negative, that's the human body creates this response of a fever, high temperatures, and hence the therapy.

8:37What therapy are we investigating in this trial is potentially beneficial for those patients that come in to see you? Will Meurer: Yeah. And, and it can go even a little further. I mean, we've heard those stories of people who fall through ice on a lake and are are under the water in the lake for a half hour, to some degree, that's, that, that coldness of that lake is, is much colder than we would do-- w- than we did in, in the IceCap trial. But that, that slows down all the body's circulatory processes, can slow down those cell death processes, which is why we sometimes see people who have these, these miraculous recoveries a- even after being under water for you know, mind-boggling amounts of time.

9:19addition, for some types of cardiac surgery they, they need to put... where they need to stop the heart to do work on, say, the aortic arch and, you know, to, to, to fix things, they put people on a bypass machine. in certain cases there, they, they know that if they cool the body down quite a bit before that, You know, they-- The fact that they have them on a bypass machine helps keep blood flowing through the brain, but there still is a chance that you could injure the brain in those types of procedures.

9:48So there are some where they will do, um, a hypothermic treatment during these planned surgeries. We We also know that in, in really, really little kids who've just been born, who maybe have a umbilical cord wrapped around their neck or something, and they don't get enough oxygen during the birth process, they have some brain damage. And those kids, you know, if you, if you cool those kids also down to about 33°F on a cooling blanket, you can limit the amount of damage they have and, you know, increase the chances that they live a normal life without any developmental problems.

10:24So there's, there's these other sort of human cases where we've we, we've, seen hypothermia be protective. A lot of people have done animal research that is more mirrors this cardiac arrest situation that has shown that, that you can... This is really one of the best ways to protect the brain. And part of that, we think, is because when, you know, we talk about these cells deciding to die, there's a lot of ways they can decide to die. And you could think, "Oh, I can get a drug that blocks one of those ways."

10:53But then the, then the, you know, the cell just goes around, you know, basically goes around the corner and takes a different pathway to dying. Um, dissimilar from cancer, where it may be like- Right this is the specific thing, and if I block that or, you know, a, a sort of monogenetic, you know, neurologic disease where you're like, "If I can stop the body from, from making that one bad protein, I can, I can stop the disease here." But there's lots of ways that the brain dies.

11:18So the th- th- the thought is that hypothermia maybe slows down multiple mechanisms. And, you know, that's, that's borne out in the animal data, but to some degree, we don't really know how to implement it people. Like, who are the people we should cool? You don't wanna cool people who aren't very injured because then you're exposing them to more time in the ICU and on sedatives and all this stuff. on the other hand, don't wanna... If you can protect somebody, you wanna cool them long enough so that You're giving that brain a chance to, to get as much recovery as it can.

11:54so they, they did some studies back in two thousand that were, were relatively small studies called the Haka study and the Bernard study, but they did have pretty eye-popping results of improving mortality. Um, they didn't use modern devices. They more or less used ice packs and, and cooling, cooling, cooling blankets, fans, things like that. But they also, in their control groups, didn't do much to control fever. So that was one of the criticisms of those studies in that the effect they saw from hypothermia more this protection from being low, was it the fact that being a little low was a good way to not go high?

12:33So that, that left-- even though the guidelines, um, that came to be after, after two thousand and two when those studies came out were favorable and saying that we should cool people for roughly twelve to twenty-four hours, there, there were these unanswered questions as to would this really work in, in a, you know, bigger population th- and also a population where the ICU was, was more diligently treating fever in a, in a control group. Scott: Yeah.

13:04Okay. So, so walking into this, the design of this trial and, and the, the design process of this trial was, it was extended, getting funding and various things. Uh, it's thought that hypothermic cooling of patients that come in after cardiac arrest, restoration of, of, uh, of the heart, of, of blood flow, they come in, does cooling them, it-- uh, it's thought that cooling is beneficial. There still remains a number of questions. Conclusive evidence of benefit is also not there.

13:38So going into this trial, it is somewhat standard of care at your University of Michigan Hospital that if somebody suffers from this, they will be cooled. So what is it that ICECAP decides to explore? I imagine it could be temperature. I could imagine how fast you get them there, whether you cool them at all, whether you just prevent this, how long you cool them. What is it that ICECAP is going to explore? Will Meurer: Yeah. I think one other thing that, that maybe I Scott: Hmm.

14:09Will Meurer: out about those early studies is one thing that they did was they focused on sort of the patients who they thought had the best chance of recovery, and these were people they thought had a cardiac arrest from cardiac causes. And that meant when, when EMS shows up, they're in this ventricular fibrillation or v-ventricular tachycardia-type rhythm, like my guy at the VA. Um, they get shocked, and their, their heart gets restored. So that's sort of one mechanism why the, why the heart starts or h- why the heart stops And that's thought to be favorable because you basically you're like a normal person.

14:48You don't know you have any medical problems. And all of a sudden, a clot flicks off to a big vessel in your coronary and bam, you drop. So your body isn't very sick from other diseases, maybe a little bit of hypertension here and there. But, you know, getting that person, you know, back and going is one thing. The other type of cardiac arrest where somebody's heart stops is what we call non-shockable arrest. And that comes from else going on with the patient.

15:15Like they have a bad respiratory problem and they get less and less oxygen. And all of a sudden, there's not enough oxygen in their bloodstream to keep the heart moving or they have a blood clot heaven forbid. And this is something that we will find came up more commonly than we thought. They take an overdose and they stop breathing. And when they stop breathing, the body is more slowly being deprived of oxygen. Whereas in that initial case of the sudden drop, you have a normal oxygen level.

15:45So even though your heart has stopped, there was a fair bit of oxygen and stuff that was pushed up to the brain. Whereas if you're not breathing for a while and a while and a while, there's even more sort of pre-injury. So when I said we don't really know much about severity, we did know that one thing. And the one limitation of the trials was those 2002 trials, they didn't think those people with the latter type, the non-shockable, had a lot of prospect for recovery.

16:14So they really only studied those who had shockable rhythms. So another thing that another big question we had is the guidelines were vague the non-shockable people. They said, please cool the people who had shockable rhythms, but the people with non-shockable rhythms, we're not sure. There's no reason to think that the brain wouldn't potentially be protected from hypothermia based on these two different mechanisms. But there was a worry that maybe these people had such a bad prognosis that if you include too many people like that in your trials, you're not going to have enough good outcomes to see a difference.

16:51Scott: Okay, so the, the, the reason for the cardiac arrest, shock, um, shockable and non-shockable is a question. Um, and then largely hypothermia. This trial-- By the way, I, I, I'm not sure we, we laid this out. When you and I are speaking right now, this trial is over, um, that we, we know the results. We are not gonna talk about the results. The results are coming out. Uh, believe they've been accepted into JAMA, but, um, that we're going to have another podcast of the results, and we're gonna talk about the results and what they mean.

17:27We wanna talk about the design, so we're setting up the design part of this. So what is it y- So you, you are going to look at two different kinds of patients, shockable and non-shockable. What is it-- What are the interventions you're assigning to a patient? Will Meurer: I think one of the things is, we arrived at this after having these meetings as part of this interesting and, and really cool regulatory science initiative that was sponsored by the US Food and Drug Administration and the, the US, uh, and the Office of the Director at the NIH.

18:03Um, we did this project called ADAPTT, which is, which is where we s- we, we started to work together. And, um, in the, the process, the, the sort of straw man design for something like ICECAP was to look at a, a, a few different cooling durations like twelve, twenty-four, and forty-eight in shockable rhythms only. we had more feedback from a variety of stakeholders who were at these meetings, it became clear that, that that was probably too narrow.

18:33There was so much uncertainty in the non-shockable people, but a, a great unmet need that we should work to try to study both of those populations at the same time. But as we emerged in terms of, you know, how we were planning the trial and what decisions we're making, we, um, to make sure that if there was a signal the shockable rhythms, that we could sort of find that even if things were different in the non-shockable rhythms. Or similarly, if because the non-shockables typically have more brain damage, maybe they need to be cooled longer.

19:10So th-those were, those were some of the things that, that came through. We really wanted-- We didn't wanna study how cold you made them. We, we focused on thirty-three degrees or roughly ninety Fahrenheit from the animal models, that was, that was sort of the best-- that was a sort of sweet spot. Some people have looked at other, you know, like thirty-four or thirty-six. And we, we, we based on our read of the, the human and animal literature, looking at depth wasn't so interesting.

19:37duration we felt was most interesting like I said, in the neonates, it was about 72 hours. There was a very encouraging study in pediatrics, which didn't quite achieve statistical significance called BABKA, but 48 hours of cooling in, you know, kids who are 18 and under, most of whom were actually two and under, 48 hours of cooling was, was quite promising in terms of improving survival. So there were those sorts of numbers. But then in that one of those first Australian studies, they got people cooled really quick, and they only cooled them for 12 hours, and they also saw great results.

20:12So we had this sort of range of uncertainty. So duration was important. But another thing that was crucially important to us was the therapeutic window. we really felt that based on the preclinical data, that it was important to get people cooled quickly. Some people come in cold, you know, obviously, you've spent a lot of your life up in Minnesota, easier to be-- easier for a patient to get cold up in Minnesota in the winter than it is in Austin in the summer.

20:45So there is some of that, but a lot of it is really, if the body's brain is injured, it, turns off your temperature center to some degree. So your body is sort of even in a relatively warm environment, body is going to get cold. So people cold early something we looked at as very important to reduce variability in the trial, right? Because if we're like, we're testing these different durations, but some people are getting cooled starting 12 hours after injury.

21:13Some people it's two hours after injury, some people it's six hours after injury. We felt that that could-- that heterogeneity could, could really sink our trial. So we did have a focus on with the hopes that, that sites would get really engaged and get devices on people quickly to have, um, cooled quickly as a condition of the trial. Because of that, and because the guidelines at the time it were-- was designed were cool everyone, we couldn't have what one would consider a classic control group, um, in terms of let's just turn-- let's just put a device on and set it to 37 degrees, you know, ninety-eight point six, and just make sure they don't get fever, you know.

21:56So that-- we couldn't do that because we requi-- we wanted people to be cooled before they were even to be eligible for the trial so that, that sites-- since sites were cooling everybody as a condition of being in the study, at least anybody with a coma or that had to be their usual practice to get into the study, that meant we could require patients to be cooled to a certain amount before they could be randomized to a duration. Scott: Okay. So we are in the ICECAP trial, we're gonna randomize people to a duration, and a critical part of all of this is that we can't do no duration, no cooling.

22:33Uh, you would slow down people that are gonna be cooled by trying to get consent or a waiver of consent or all of that. Standard of care is to cool them. So everybody is cooled in the trial, but you're going to vary the length of time they're cooled in the trial, um, uh, within this. And initially, uh, a- and, and going back to this-- By the way, the ADAPT-IT project that you mentioned was, was a fabulous project, and I think we had six different trials, and the goal of that project was to explore innovative designs being brought to clinical trials in the emergency room setting and to study barriers to bringing in innovative design.

23:17And, uh, interestingly, I think the number one barrier was statisticians, but that, that's a, a topic for a different day. Um, uh, and this-- there, there was, there was research, and we, we had, uh, IRB approval to study the people building the designs as to, to what were barriers and what were going on So I remember the initial design that I simulated for this trial was randomizing patients to twelve hours, twenty-four hours, and forty-eight hours.

23:47And initially, it wasn't the two populations, so we'll kind of ignore that part. And, uh, we had a dichotomous outcome of their ninety-day MRS status, and we simulated those trials and showed a number of those results, and a lot of times it didn't really answer the questions. There was a great deal of, "Wow, boy, I wish we had more on the smaller ones in this case." Is even somewhat of an optimal curve that it kind of goes up at twenty-four and kind of comes down, left huge uncertainty whether this was flat, whether what the shape of this curve was.

24:22So there was a desire to have more durations, focusing patients where the best benefit was being, being seen. And so as you described, the next generation of this trial was, first of all, changing the endpoint to analyzing the whole scale, and we'll get to how we did that. But we opened up six hours, twelve hours, eighteen hours, twenty-four hours, all the way up, I think, originally to eighty-four and ninety-six hours. There were twelve different durations that a patient could be randomized in version number two of this trial that we started to simulate.

25:09Will Meurer: And yeah, and then I think this was one of the really great things about the Adaptive project was that by sort of illustrating design first, you could show people like Oh, I don't know. At the end of that trial, I'm gonna be sad or have this anticipated regret as we, we talk about it. Or, or doing the pre-mortem, right? If we do that twelve, twenty-four, forty-eight trial and it's, it's, it's sort of like, "Oh, we should have gone out to seventy-two," or, "Oh, maybe, maybe six would've been better."

25:39Or so, so, so that-- You know, I think that's an important concept. I think the thing that also is, you know, I think really fascinating is that, you know, by seeing the way the trial could come out, then you get people together and they're like, "Gosh, we need to, we need to do something a little different." And the other thing, though, is you do have to put this-- And, and sometimes I think, again, when you say like statisticians are the, are the barrier, you, you're also working with, hey, the guidelines say cool everybody for twenty-four hours.

26:12So to some degree you could say, yeah, let's look from ninety-six to zero. from a statistical perspective, you know, the most efficient way to, to do that is you're gonna start putting people on both ends to sort of see like, oh, is this, i-is this possibly flat or, or maybe there's gonna be an upslope in the middle, but, but, but, you know, kind of go into the ends and, and fill in. But since those are far from, you know, both those are far from what was guideline recommended at the time, the human constraint on the model was like, we do have to do it this way because it, it's not ethical to all of a sudden cool people for ninety-six hours.

26:47Um, you know, people who are in ICUs, you're gonna-- You know, if they start to wake up, you're gonna want them to let, let them wake up. So, so the, the... You know, if it's only six hours of cooling, the guidelines say twenty-four. Patients are gonna be like, "Why are you putting my family member on such a small duration?" So, so we did have this constraint because there was, you know, real recommendations for practice that we... You know, I think in retrospect sometimes people say, "Well, like, why didn't you just evenly distribute them across ten arms?"

27:15And it's like, wasn't... You know, based on what we knew about the science at the time we were coming up with the design and starting the trial, you know, that wouldn't have been ethical. So that, so that's I think, you know, important, and I think that was one of the things. You know, you would show us a d- Scott: Yep. Will Meurer: a little too, too long on this neutral case. Like, why is it, why is it putting people over there?" And then you'd say, because it wants to know, and that's how it's gonna find that slope of that line."

27:46And say, "Well, like, let's, let's, let's, let's see if we can, you know, nudge that backwards so that it's... It needs to have stronger evidence that there's an upslope, you know, between, you know, durations that we've used before, twelve to forty-eight, before it starts looking at those longer durations." So I think that was so crucially important. It took a lot of, you know, time and energy to go back and, and think of those things. But, you know, it's one of those things, though, when people look back at the design, sometimes they're like, "Hey, why did they do that?"

28:16But once you know the results- Like, the reason we were doing the trial was we didn't know the results. We didn't know what this was gonna look like. Um, so we wanted it to be flexible to a variety of different truths and be able to get us, uh, an answer that could be very useful to us under a variety of these scenarios, whether it was like up sloping late, up sloping early, flat, going down. And I think that was something that, that when people say, "Well, what-- why'd you do all this complicated stuff?"

28:46You know, this is something that's come up in adaptive designs. I think like the ASTON trial of the neutrophil inhibitor for stroke, I think is, is sometimes cited. It was a really innovative design. They, they went through so many different dose tiers in their design, and I thought it was like an amazing trial. But then critics later are like, they could have learned that with three doses and, you know, a third of the patients." But didn't know that in advance, right?

29:11Like, if they had done three doses, maybe they would have tested five-- you know, three different ones after that initial trial. As opposed to they got to a very convincing answer that in, in the population they were testing, their agent, you know, didn't, didn't help those stroke patients. So, so I think sometimes when we have adaptive designs that, that kind of go more into that, neutral space, people are, people are like... Or even adaptive designs that show something positive, people are like, "Oh, well, it would've been much easier to just assign them to those two groups," right?

29:45But it's like, Scott: Right, right, Will Meurer: that when we started. Scott: right. Right. Right, right. Okay. So i- through the simulations, a- as you describe this, quickly, by the way, 84 and 96 hours dropped out, largely for operational things, that people are in the, for five days in the, the, the emergency room, and it would've been awkward to do the trial where they go to the ICU as... So we dropped those off, and we-- I, I remember showing a simulation where initially we simulate to those same three arms, 12, 24, and 48, and then we do response adaptive randomization.

30:21We allocate patients where they're most likely to be benefit across that curve. If the low doses are doing the best, we put more there, refining that later ones. And I showed an example, a single trial where the curve went up, it was flat, it went down a little bit, but then it started to go back up. I was using a smoothing spline across the, the 12 durations. And it started to assign patients at 72 hours. And the clinicians all said, "Nope, we would never do that," that that, that dose response curve is not believable.

30:57There's the-- It's, it's not conceivable that the curve across durations would start to decline, that patients do worse as you cool them more, and all of a sudden it starts to go up again. And that was a, that was a, a, a really important insight. Also, uh, on the, on the other side, largely it was that this curve is gonna be an inverted U, that if this is beneficial, or if it's not beneficial, it fits on this curve, that there's gonna be a point where cooling more is beneficial.

31:32It may then be flat for some length of time, and then it's gonna go down. And we know at the extremes those would be the cases. If you cool somebody for 30 days, they're not going to do well, and, and we know that it's gonna get worse. Now, so that became the analysis model of this trial, that it's an inverted U dose response. It has a-- it can have a flat area. The important part is all of the, the, the 10 doses could be on the upslope. So we modeled it so the doses are somewhere on that inverted U.

32:04They could all be on the upslope, and 72 hours is the best. They could all be on the downslope, and cooling is bad. The more you cool them, the worse they get. They could all be flat, that from six to 72, it doesn't matter, it's flat. Or it could go up and be flat, it could be flat and go down. That's the model that drives the trial And what's really nice about that, so there's a Bayesian model of this inverted U th- that allows the doses to be ordered somewhere on that scale.

32:33And what we're looking for is the smallest dose that achieves the highest level, and that's defined by this, the, as this optimal dose that's defined by the curve. Because we know if it's getting flat, there's-- you don't wanna go bigger. There's no reason to go bigger. It's not gonna go flat and then up. It can't in this shape. So we use that in response-adaptive randomization to allocate patients, and that was the next version of this. And we added in, you, you addressed these gu- guardrails that we didn't wanna start with people on six hours, and we didn't wanna start with people on 60 hours or 72 hours.

33:15If the evidence was building that the dose response was continually increasing through up to 60, and the algorithm thought it was likely that was the best, we would open that arm with guardrails, and we would open six with guardrails if it appeared that six might be the most effective dose or this optimal dose. Like, if it looks really flat, we could open six, only with adaptive conditions in the trial, is how we started to migrate the design. Then...

33:52Yeah, yeah, go ahead. Will Meurer: no. No, no, you can, you keep Scott: I was gonna say, then it became we want to investigate both non-shockable and shockable, and the concern is that this optimal place is different for shockable and non-shockable. As you set up, it might be, depending on the etiology for why the person went down, you might wanna cool longer or shorter within that. So we ended up moving the design to having the same duration response model modeled separately in the two populations and having different response adaptive randomization probabilities by rhythm type.

34:35Will Meurer: Yeah, the thing I was gonna say is, you know, that's another thing, right? People, you know, would say, "We don't think this duration response can go up and down." But somebody later might, like, do some animal research and say, "Oh, gosh, biologically, you need to cool during this reperfusion period, and then maybe you need to cool later during this, you know, period where the brain is getting swollen." But again, that's not one of the arms we had, where it's like cool from six to twelve, pause, and then if you haven't woken up, cool again from, you know, seventy-two to ninety-six.

35:10One of the things that, that I sort of brought up, I think, back when we were having these planning meetings is, gosh, wouldn't it be nice if there was some way that we could tailor the treatment? You know, this is, this sort of Goldilocks approach to cooling. Like, if we had some way to measure the brain and, and, oh gosh, it's, it's crying out to us as we rewarm somebody. Let's, oh, oh, let's, let's like, then make them cool longer. And again, that was a lovely idea, but we as a scientific community at the time said, "Hey, Will, that's cute, but we don't know enough about how this works to do something that complicated that, that might take a billion patients."

35:48Um, but we have earnest uncertainty in these, you know, in these durations that we're testing and whether there's, know, I think, you know, as, as we'll get to next, while we don't have a control group, if everything's on the upslope, and it's a pretty good upslope, that's a, it's a pretty good way to connect the dots with a, with a no cooling group. Um, so, so I think have to make... You know, we did th-think that there could be individual designs that, that maybe could be better for patients, but we didn't have any of them off the shelf, and didn't have a good way to, to sort of think about how we could implement something like that, that sort of let me cool them until their brain tells me It's ready to wake Scott: We weren't ready.

36:35Yeah Will Meurer: we, you know, one of the other constraints that we all have in, in this space that is also something that's sort of really interesting is there is a lot of pressure in, in the US healthcare system in particular kind of get bored with providing critical care to somebody who might not wake up say, "Yeah, you know, Uncle Joe's lived a good life, but sure if he's gonna wake up." And then having people wanna do care limitations and remove people from technologic support which, which, which commonly happens.

37:10But in a trial like ICECAP, that's a huge problem, right? Because these people aren't being given an opportunity to wake up. of the potential mechanisms... You know, I talk about biological mechanisms of cooling. One of the potential mechanisms of cooling, at least in the clinical trial s-sense of potentially improving outcomes, is the longer you cool-- You can't, you can't pull the plug on somebody while they're cold. You have to, you know... So, so if you have a longer time period, you're basically, you know, sort of creating this sort of reverse shot clock of, you gotta wait at least this long before you, you take a shot at letting this person wake up.

37:50And in some of the trials that have been done, have been waking up, you know, twenty-two to thirty days after the injury. Now, that's not to say that every single patient who has a cardiac arrest should be given twenty-two to thirty days to wake up, but, but many of them aren't, aren't giving, being given more than two. And that's, again, that, that, you know, certain European countries, people are much more willing to give it a, give it a week or two.

38:16Um, again, not trying to make this a, a sort of value judgment on different societies, but it's an observation that, that people do handle these things a little differently in places. Um, and, and there's also a lot of clinicians who are like, "I'm sure they won't wake up." But if you tell that to everybody at day two, and sometimes it takes people five to twenty days to wake up, you're gonna be right, none of your patients wake up. But some of them would have if you had given them longer.

38:43So, so we also have Scott: And Will Meurer: of, you know, social element of the trial and, and working to do, you know, another intervention. You say, "Well, why did you, you, you pick duration?" 'Cause that was most interesting. We tried to limit variability on this care limitation by having clinical standardization. Say, you know, "Please talk to us if you're doing this." You have to have a defined protocol to prognosticate whether you're doing an EEG, you're doing brain imaging, you're doing blood tests to make sure that if you, if you wanna tell a family that this person isn't gonna wake up, you do have some additional evidence that sort of backs that up, that it's, it's, A, it's pretty unlikely that they're gonna wake up.

39:21So that was another aspect of the trial. It was a feature of some concurrent European trials that, that went on, that they did, they did that in a standardized way. So that's another thing, but from a study design perspective people don't complete their duration of cooling because of early care limitations, it introduces, um, you know, noise into our trial. You know, our trial has less ability to pick up a treatment effect when those observations aren't contributing really to the, the treatment effect estimate.

39:51Scott: we, we, for, for especially the statisticians out there, we do intend to treat. So if a patient is, is g- is assigned forty-eight hours and dies at twelve hours, they're in the forty-eight-hour arm, and their outcome is that. If they somehow come off of it at twenty-four hours, they're forty-eight hours. So it's intent to treat, uh, from the arms of that. Um, I, I, yeah, I think it's an or-- in a really important part in the interactions of this, I remember we, we went to the NIH presenting to get this funded.

40:25I think there was discussion about... Sorry, at that time, we went with members of the FDA. The FDA really wanted this trial to run. Uh, Bram Zuckerman, in particular, really wanted this trial to run. Now, medical devices out there have been approved that they cool a patient. That's not tied to clinical benefit. It doesn't say it's good to cool people, but you've demonstrated you can cool somebody to thirty-three degrees And these are being used, and so there's not a great incentive for devices to run this trial, to fund this trial, so they're not gonna fund this trial.

41:05There might even be a disincentive to, to, to fund this trial. Um, the FDA wants this trial to run, and so we went to the NIH, and the FDA went, uh, on behalf of the design that we'd really like to see this trial run, which was sort of a unique experience, uh, uh, in, in the whole interactions of getting this trial run. And eventually this trial was, uh, funded by the NIH. Will Meurer: Yeah. I, I think the FDA even a little more excited so to, so to speak about it, because really the Scott: Yep.

41:46Will Meurer: So the use of them to-- You, you can set a different target, but really the idea was that they were to keep people at normal temperatures or pay-- or potentially warm people up who have environmental hypothermia. So to some degree-- Well, and, you know, every time I've given a presentation about ICECAP, I, I put in that disclosure, "I will discuss off-label uses of these devices," because, you know, the, the way that their label was.

42:09So the FDA felt that it was, uh, important from a regulatory science perspective to learn more about the safety of these devices when being used outside of their label. Um, so, so that was-- That, that gave them additional enthusiasm for our design. And you're right, it was really unique, I think, to have FDA I think FDA does a lot of great things. I think they can be great scientific partners, and I think in this case, this is a great example of that.

42:35Like, in that they were interested in doing what's right for patients, but, but learning in an unbiased way through a clinical trial where all the adverse events are being adjudicated, people are-- the outcome assessors are blinded to the duration of this cooling device that they were subjected to and so forth. So, so a lot of real positives. I mean, it was, it was, it, a delight working with them on it. And, you know, I, I was the sponsor of the IDE, so I've had, had great interactions with them.

43:02They're really, really thoughtful scientists there. Scott: Okay, so let's, let's summarize the design because, uh, uh, uh, our listeners are gonna tune into this, and then they're gonna tune into the results, and we'll do a podcast of the results. So this is a design of eighteen hundred patients combined across rhythm types, where initially the allocation is twelve, twenty-four, and forty-eight hours, equal randomization. After two hundred patients, an interim analysis is done.

43:34The Bayesian model is fit for both ris-- rhythm types. We do multiple imputation of patients with thirty days MRS status projecting to their ninety-day status We have 90-day MRS as the primary endpoint, and we use a weighted scale of the MRS for, for analyzing that, not a dichotomization of that, so a weighted scale. At the interim analysis, updated randomizations are made to the different durations. That is done every fifty patients in the trial that these-- the RAR is updated throughout the course of the trial.

44:17There's a possibility of opening up, uh, them on the right or the left. So the, the ones at the beginning, twelve to forty-eight are open and can be, and it can be allocated to right away, and anything in between that by every six hours. And certain conditions could open up six hours. We, of course, we talked about opening up zero, but that was not a possibility. So it could open up six. We talked about that in the design stage. And then it could open up sixty or seventy-two on the other end if this appears to be a continual increasing, um, uh, duration response.

44:55There is no early success. There's no stopping because we've determined the right answer. There is futility if there's, uh, comes to be at least a fifty percent probability that six hours is the best thing to do, we'll stop a rhythm type. And we, we call it futility. It's largely that there's reasonable evidence that there isn't an increasing duration response curve. The two primary analyses are this, are what is the optimal duration to cool that comes from the Bayesian model, and is there an increasing duration response?

45:34If there's an increasing duration response, if twelve is better than six and eighteen is better than twelve, it gives evidence without a zero arm that cooling is beneficial. And the FDA understood the non-non-zero arm, and they understood this as a, as a signal that cooling is beneficial to patients if there's an increasing relationship with length of cooling. Within that is part of the primary analysis, uh, in the trial and the two rhythm types.

46:08Have, have I, have I summarized the design appropriately? Will Meurer: Yeah, no, but we, we maybe take a brief little tangent into the, uh, weighted mRS. And I think, you know, others, you know, other, others have probably seen this in, in the stroke world. Scott: Yep. Will Meurer: for stroke, uh, we developed this weighting scale for, for ICECAP, um, a little earlier than the strokes-- the stroke one, m- m-- you know, emerged. In the stroke one, they, they talked to clinicians and, and patients and families to develop a series of we-- a series of weights for the, the mRS states.

46:43And, um, in, in, in pedia or in adult ICECAP, we, we set these sort of based on, on cl-- on what the clinicians thought with the goal of accomplishing two things Can we find people who more or less wake up, you know, their mRS is, is, is, you know, sort of better than four? And amongst those who wake up, can we distinguish amongst the people who have really excellent outcomes? I think when we commonly dichotomize, it's like you get full credit at a 0 full credit at a 1 full credit at a 2 and all of a sudden at a 3 you get no credit.

47:20It's the same as being dead. And that, in this disease, we felt was, was the possibility of showing important improvements. Because someone with an mRS of three, if they had a really severe stroke or severe stroke, had a ve- really severe cardiac arrest, at n- at, at three months, that might be a very good outcome, and they actually may have a, a potential for future trajectory. And we're doing a study called POST-ICECAP um, that we designed to actually live after ICECAP.

47:49initially, it was following patients after their three-month follow-up, but now it's following people at three, six, nine, and twelve months to look at that trajectory of recovery over time. And, and there are certainly patients for whom an mRS of three is, is, is a r- is a really, is a win in terms of their severity of, of, of injury. So, so we did design this weighted scale. It's very similar to the utility-weighted scale that is used, that was used in DAWN and DEFUSE and other stroke trials.

48:15Um, it's subtly different, but it, it, it's-- the, the concept is the same, even though we arrived at it for a scientific reason as opposed to inducing it from sort of Clinician and patient's, uh, preferences. Scott: just for disclosure of what it is, the MRS of zero, which is the best outcome, you get 10 points. A one, you get nine points. A two, you get eight points. A three, you get six points. So the two to three difference was considered greater.

48:43And then below three for four, five, and six, you get zero points, was, was, is the, the, the scale used, the weighting of that used in the trial. Okay, and, and we should, uh, highlight that MUSC and Sharon Yates did, uh, ran this trial. Uh, she's the-- they're the data coordinating center, did a tremendous job o-on this, um, in the trial. So a complex mult-- many interim analyses done during the trial, and they did a fantastic job, um, uh, running the trial.

49:18But we can't... Will Meurer: thing, like sometimes people are like, "Oh gosh, turning around an interim analysis to change your Scott: And... Will Meurer: a data freeze." And, and you know, they were-- they, they would, they would turn it around in a day Scott: Yeah. Will Meurer: you know, a Scott: Yep. Will Meurer: really. And it was-- They, they know it was coming, but, you know, it's Scott: Yep. Will Meurer: protocol choice we made to say we are gonna do this every Scott: Yep.

49:43Will Meurer: Um, know, we did, we did also design a pediatric trial that has many features that are similar to adult ICECAP, but some that are different. Um, and one of them is that because there was more equipoise in that trial, it does have a no cooling group. It has a zero-hour duration. Goes all the way out to ninety-six 'cause of that data from neonates where seventy-two to ninety-six worked well in them. But one thing is we did say that the interim analysis would be every, approximately every ten weeks to just make it a little bit more predictable, um, and nice.

50:12But, but, but Dr. Yates and the team at MUSC, were phenomenal and, um, we were always keeping our eye on that. And but, but yeah, but it would, it would change, you know, as an emergency physician and somebody who works in the ICU, and I take stroke call, I'm like, "Oh, I gotta do something in the middle of the night on a Tuesday." I'm used to that. Generally, and again, this is not a slight on academic biostatisticians, that's not typically part of their workflow.

50:37Um, but, but they, they, they got everything going so well, and it was, it was just a delight. Scott: Yeah. Yeah. Yep. Okay. We, we need to stop now because we'd start telling results. So look for ICE CAP results, uh, coming when we do another interim analysis, which we love to do here. So thank you, Will, and I look to, to see you very shortly. Uh, and thanks everybody, and, uh, thanks for joining us. Until next time, we are here in the interim.