WEBVTT NOTE This file was generated by Descript 00:00:00.000 --> 00:00:03.359 Judith: Welcome to Berry's In the Interim podcast, where we explore the 00:00:03.359 --> 00:00:07.510 cutting edge of innovative clinical trial design for the pharmaceutical and 00:00:07.510 --> 00:00:10.180 medical industries, and so much more. 00:00:10.819 --> 00:00:11.529 Let's dive in. 00:00:12.750 --> 00:00:13.470 Scott: All right. 00:00:13.470 --> 00:00:16.830 Welcome everybody back to In the Interim. 00:00:17.870 --> 00:00:22.630 Today, we are going to talk about, uh, a really cool trial. 00:00:22.700 --> 00:00:24.260 Uh, and, and I, uh... 00:00:24.260 --> 00:00:28.520 By the way, I'm your host, Scott Berry, and I have a guest 00:00:28.520 --> 00:00:32.270 today, and I'll introduce the guest as I introduce the topic. 00:00:32.930 --> 00:00:39.490 The topic today is the ICECAP trial, and ICECAP is, you know, if I, if 00:00:39.490 --> 00:00:45.300 I put together of, of doing this for 25 years, sort of my, my five 00:00:45.300 --> 00:00:48.430 favorite, three favorite, 10 favorite, whatever, ICECAP is on there. 00:00:48.460 --> 00:00:51.270 This is a, a very, very cool trial. 00:00:51.270 --> 00:00:51.560 It's a... 00:00:51.740 --> 00:00:56.040 I, I think the trial design, the scenario, very cool. 00:00:56.140 --> 00:00:58.340 And we're gonna talk about that trial design. 00:00:58.770 --> 00:01:04.640 And, uh, joining me to talk about that trial de- de- design is Will Moyer. 00:01:05.050 --> 00:01:09.550 Will is a professor of emergency medicine and professor of neurology 00:01:09.930 --> 00:01:11.650 at the University of Michigan. 00:01:11.990 --> 00:01:15.730 He's also a medical and scienti- uh, statistical scientist 00:01:15.730 --> 00:01:16.800 here at Berry Consultants. 00:01:17.150 --> 00:01:19.420 So Will, welcome to In the Interim. 00:01:20.263 --> 00:01:21.963 Will Meurer: Yeah, I'm so, uh, happy to be here. 00:01:22.950 --> 00:01:27.770 Scott: And, uh, uh, sometimes I ask my guests, "Are you a Bayesian?" 00:01:28.960 --> 00:01:33.940 And if, if you have video access to this, there are some people that have only 00:01:33.940 --> 00:01:39.610 audio access to this, I don't need to ask that question as, as Will is wearing 00:01:39.610 --> 00:01:41.700 a T-shirt with Bayes' theorem on it. 00:01:41.700 --> 00:01:45.930 So he is declaring his allegiances just from the start. 00:01:46.700 --> 00:01:48.940 And ICECAP is a Bayesian trial. 00:01:49.480 --> 00:01:51.660 Uh, the final analysis is Bayesian. 00:01:51.660 --> 00:01:52.780 The trial is Bayesian. 00:01:52.780 --> 00:01:55.910 But let's, let's get to the ICECAP trial. 00:01:56.300 --> 00:02:01.850 The, the story of the design of this trial is as fun as the design itself. 00:02:02.520 --> 00:02:07.850 So let's talk about, uh, uh, we'll, we'll talk about the development of the trial. 00:02:07.880 --> 00:02:12.300 But to give people a sense, what, what is the ICECAP trial? 00:02:12.300 --> 00:02:14.200 What is the, the syndrome? 00:02:14.570 --> 00:02:16.430 The, what are we treating in ICECAP? 00:02:18.193 --> 00:02:18.543 Will Meurer: Yeah. 00:02:18.543 --> 00:02:23.393 So, you know, when we take like high school or middle school health 00:02:23.393 --> 00:02:27.463 class, we know that, you know, if your brain stops getting oxygen, 00:02:27.543 --> 00:02:29.293 um, bad things happen to it. 00:02:29.363 --> 00:02:32.603 Somet-- You know, people are lear-- you know, maybe learn, gosh, in, 00:02:32.603 --> 00:02:35.993 in three, four minutes, your brain is gonna be damaged irreversibly." 00:02:36.433 --> 00:02:40.643 Um, so when people have problems with their heart such that their heart suddenly 00:02:40.643 --> 00:02:45.093 stops beating, like they're having a heart attack, there's a blocked artery, 00:02:45.433 --> 00:02:48.463 or for whatever reason, the electrical information in the heart just goes 00:02:48.463 --> 00:02:53.323 haywire, um, all of a sudden there's no blood flowing up to the, up to the brain. 00:02:53.463 --> 00:02:58.213 You know, the body goes down um, hopefully there's somebody nearby 00:02:58.213 --> 00:03:01.903 if that happens to you so that they can start CPR and potentially get 00:03:02.443 --> 00:03:05.503 An automa-- you know, an automated external defibrillator and restart 00:03:05.503 --> 00:03:07.203 the heart as, as quickly as possible. 00:03:07.603 --> 00:03:10.213 Um, when I was a medical student at the Cincinnati VA, I was just 00:03:11.113 --> 00:03:16.463 by the ER one night, um, and, and literally a guy, um, went into cardiac 00:03:16.463 --> 00:03:18.193 arrest just as we were walking by. 00:03:18.243 --> 00:03:22.563 And somebody got the, the old school paddles, went up to the guy and, 00:03:22.623 --> 00:03:24.493 and zapped him, and he just... 00:03:24.933 --> 00:03:27.463 He woke up, screamed, like, like... 00:03:27.553 --> 00:03:32.713 And he, he, he, he-- We got to him before he developed any brain damage. 00:03:33.213 --> 00:03:36.543 But in, in lots of cases, um, we don't get the heart restarted that 00:03:36.573 --> 00:03:41.713 quickly, and because of that loss of blood flow, the brain is, is damaged. 00:03:41.973 --> 00:03:47.703 And, we don't know, though, at the moment that people get the heart restarted 00:03:48.723 --> 00:03:50.593 how damaged that brain is gonna be. 00:03:51.043 --> 00:03:53.433 All the cells that are inside the brain, you know, we think of 00:03:53.433 --> 00:03:56.853 neurons, there's blood vessel cells, there's connective cells there. 00:03:57.333 --> 00:04:00.403 These are all hurt by this, this lack of oxygen, but they're 00:04:00.403 --> 00:04:02.233 not all necessarily gonna die. 00:04:03.633 --> 00:04:08.203 the idea of treating cardiac arrest, you know, first you 00:04:08.203 --> 00:04:09.073 have to deal with the heart. 00:04:09.103 --> 00:04:13.733 If you don't get the heart restarted, you, you know, it, it's very hard to, to live. 00:04:13.733 --> 00:04:15.083 It's, it's really sort of game over. 00:04:15.333 --> 00:04:19.083 But if you get the heart, heart restarted, then the most common 00:04:19.083 --> 00:04:23.173 way people die is because of brain injury, so that they don't wake up. 00:04:23.793 --> 00:04:30.743 So one of the things that we know is that when the brain is injured, um, 00:04:31.533 --> 00:04:35.083 temperatures like fevers really harmful. 00:04:35.113 --> 00:04:38.203 So the, you know, the way I think about this is there's a bunch of 00:04:38.203 --> 00:04:41.343 these neurons and other, you know, other cells inside the brain. 00:04:41.823 --> 00:04:42.593 They've been hurt. 00:04:42.983 --> 00:04:46.433 They're still functioning, but they're, they're, they're maybe not happy about it. 00:04:46.433 --> 00:04:51.063 They haven't decided, like, should I, should I turn myself off? 00:04:51.063 --> 00:04:53.783 Should I go to the-- you know, hit the self-destruct button because 00:04:53.783 --> 00:04:56.563 the situation is bad and I'm, I'm not gonna be able to recover? 00:04:56.953 --> 00:04:58.673 Or should I give this a little more time?" 00:04:59.293 --> 00:05:03.063 Um, one way of thinking of this, it's, you know, it's an oversimplification 00:05:03.063 --> 00:05:07.303 of biology, is that when the temperature goes up, more of those 00:05:07.303 --> 00:05:11.753 cells decide, you know, they're done, that they can't survive this. 00:05:12.113 --> 00:05:16.043 And we see this not just in, in the brain injury from cardiac arrest, 00:05:16.533 --> 00:05:20.883 um, but we also see this after stroke, traumatic brain injury. 00:05:21.253 --> 00:05:28.113 Anytime there's a serious hit to the brain, is, um, you know, this really 00:05:28.113 --> 00:05:30.283 common situation that fever is bad. 00:05:30.683 --> 00:05:32.963 And these are sick patients in the intensive care unit. 00:05:32.963 --> 00:05:36.483 They're on mechanical ventilators, so there's plastic and, you know, coming 00:05:36.483 --> 00:05:38.523 out of all sorts of body orifices. 00:05:38.803 --> 00:05:42.753 So the- they're very-- people are very prone to infection in this fragile state, 00:05:42.753 --> 00:05:45.283 so these, these fevers can be quite bad. 00:05:46.463 --> 00:05:51.633 so in the early two thousands, um, well, even before that, like way back... 00:05:51.795 --> 00:05:52.795 Scott: let's back up a little. 00:05:52.795 --> 00:05:56.065 So these are patients suffer A cardiac arrest. 00:05:56.065 --> 00:05:59.775 There are other, there are other reasons why somebody has lack of blood flow, and 00:05:59.775 --> 00:06:03.295 so the whole therapy that we're gonna investigate might be interesting in there. 00:06:03.295 --> 00:06:07.245 But in this trial, we're looking at they suffer cardiac arrest. 00:06:07.485 --> 00:06:09.905 For some period of time, there wasn't blood flow. 00:06:10.285 --> 00:06:13.495 It gets restored, so these are patients that have been restored. 00:06:13.495 --> 00:06:16.535 They come into the emergency room where Dr. 00:06:16.535 --> 00:06:18.695 Moyer is, uh, in that. 00:06:18.825 --> 00:06:21.615 And, and then the question is, what do you do? 00:06:22.225 --> 00:06:23.945 Uh, do we have therapies for them? 00:06:23.995 --> 00:06:25.195 Is that right? 00:06:25.195 --> 00:06:26.005 Did I get that right? 00:06:26.698 --> 00:06:27.098 Will Meurer: Yeah. 00:06:27.128 --> 00:06:27.378 No, 00:06:27.495 --> 00:06:27.735 Scott: Okay. 00:06:27.738 --> 00:06:28.248 Will Meurer: that's right. 00:06:28.385 --> 00:06:28.625 Scott: Okay. 00:06:28.908 --> 00:06:30.128 Will Meurer: and this is like a, a... 00:06:30.278 --> 00:06:31.988 This is damage to the whole brain. 00:06:32.018 --> 00:06:34.488 So if you've-- You know, a lot of people are familiar with 00:06:34.488 --> 00:06:35.918 stroke and stroke research. 00:06:35.998 --> 00:06:39.038 In there, i-in stroke, you have damage to one part of the 00:06:39.095 --> 00:06:43.095 Scott: Yeah. 00:06:43.138 --> 00:06:46.818 Will Meurer: that case, people usually are awake, and you can measure 00:06:46.818 --> 00:06:50.108 how big a stroke they have by how, you know, how weak their arm is. 00:06:50.258 --> 00:06:53.698 You know, this is part of, you know, what I do in my, in my daily work, or 00:06:53.698 --> 00:06:57.118 at least, you know, a few times a, a month when I work on the stroke team. 00:06:57.118 --> 00:07:01.168 So stroke, you can kinda quantify the severity with this, you know, 00:07:01.168 --> 00:07:03.058 with like an NIH Stroke Scale exam. 00:07:03.358 --> 00:07:06.508 You can do a special type of imaging test, which, which, which you, you've 00:07:06.508 --> 00:07:10.918 all worked on, a CT perfusion that can say, "Look, this, this is the 00:07:10.918 --> 00:07:12.878 volume of the brain that's at risk." 00:07:13.168 --> 00:07:15.888 Whereas in cardiac arrest, we don't have a m- we don't have a 00:07:15.888 --> 00:07:17.898 real true marker of the severity. 00:07:17.928 --> 00:07:21.188 It's like the person looks comatose. 00:07:21.188 --> 00:07:22.068 They're not responding. 00:07:22.068 --> 00:07:25.148 Maybe they're looking around a little bit, but they're not able to follow commands. 00:07:25.458 --> 00:07:30.098 But we don't have a sense as to how big a hit their brain took and 00:07:30.098 --> 00:07:32.218 whether or not they can, can recover. 00:07:32.588 --> 00:07:36.848 Um, so that's why we wanna try to implement therapies that, that protect 00:07:36.888 --> 00:07:43.328 the brain or, or can, you know, limit the damage, um, you know, that would be 00:07:43.328 --> 00:07:45.738 what can help, help improve the outcomes. 00:07:45.778 --> 00:07:48.588 So that's, you know, that's sort of the stage. 00:07:48.948 --> 00:07:51.418 You know, the patient has been resuscitated by usually 00:07:51.418 --> 00:07:53.018 the paramedics in the field. 00:07:53.488 --> 00:07:57.138 Um, sometimes a bystander brings it, like an AED, and they g- 00:07:57.178 --> 00:07:58.258 they get the heart restarted. 00:07:58.258 --> 00:08:00.628 And then they're- they've come to the emergency department. 00:08:00.668 --> 00:08:04.368 And unlike that guy at the Cincinnati VA who woke up screaming that his 00:08:04.368 --> 00:08:09.188 chest hurt, these folks are, you know, on a mechanical ventilator, you 00:08:09.188 --> 00:08:13.708 know, and really, you know, not, not able to speak or, or follow commands. 00:08:13.708 --> 00:08:16.598 And that would be, be the coma after cardiac arrest 00:08:16.598 --> 00:08:18.118 that is, is the brain injury. 00:08:18.935 --> 00:08:19.235 Scott: Okay. 00:08:19.485 --> 00:08:26.435 And, and the heat you described that could accelerate neuron death and it considered 00:08:26.435 --> 00:08:34.395 to be a negative, that's the human body creates this response of a fever, high 00:08:34.395 --> 00:08:37.685 temperatures, and hence the therapy. 00:08:37.685 --> 00:08:42.085 What therapy are we investigating in this trial is potentially beneficial for 00:08:42.085 --> 00:08:43.905 those patients that come in to see you? 00:08:45.058 --> 00:08:45.508 Will Meurer: Yeah. 00:08:45.628 --> 00:08:48.068 And, and it can go even a little further. 00:08:48.068 --> 00:08:52.056 I mean, we've heard those stories of people who fall through ice on a lake 00:08:52.096 --> 00:08:56.628 and are are under the water in the lake for a half hour, to some degree, that's, 00:08:56.838 --> 00:09:00.818 that, that coldness of that lake is, is much colder than we would do-- w- 00:09:00.818 --> 00:09:02.198 than we did in, in the IceCap trial. 00:09:02.198 --> 00:09:07.298 But that, that slows down all the body's circulatory processes, can slow down 00:09:07.298 --> 00:09:10.648 those cell death processes, which is why we sometimes see people who have 00:09:10.648 --> 00:09:15.668 these, these miraculous recoveries a- even after being under water for you 00:09:15.668 --> 00:09:19.018 know, mind-boggling amounts of time. 00:09:19.768 --> 00:09:24.178 addition, for some types of cardiac surgery they, they need to put... 00:09:24.267 --> 00:09:27.508 where they need to stop the heart to do work on, say, the aortic arch 00:09:27.508 --> 00:09:31.648 and, you know, to, to, to fix things, they put people on a bypass machine. 00:09:32.418 --> 00:09:35.958 in certain cases there, they, they know that if they cool the body down 00:09:35.958 --> 00:09:39.918 quite a bit before that, You know, they-- The fact that they have them 00:09:39.918 --> 00:09:44.468 on a bypass machine helps keep blood flowing through the brain, but there 00:09:44.468 --> 00:09:48.058 still is a chance that you could injure the brain in those types of procedures. 00:09:48.388 --> 00:09:51.968 So there are some where they will do, um, a hypothermic treatment 00:09:52.348 --> 00:09:54.287 during these planned surgeries. 00:09:54.347 --> 00:10:00.588 We We also know that in, in really, really little kids who've just been born, 00:10:01.028 --> 00:10:04.228 who maybe have a umbilical cord wrapped around their neck or something, and they 00:10:04.228 --> 00:10:09.078 don't get enough oxygen during the birth process, they have some brain damage. 00:10:09.448 --> 00:10:12.998 And those kids, you know, if you, if you cool those kids also down to 00:10:12.998 --> 00:10:18.298 about 33°F on a cooling blanket, you can limit the amount of damage they 00:10:18.298 --> 00:10:22.168 have and, you know, increase the chances that they live a normal life 00:10:22.168 --> 00:10:23.878 without any developmental problems. 00:10:24.118 --> 00:10:27.038 So there's, there's these other sort of human cases where we've we, we've, 00:10:27.668 --> 00:10:30.528 seen hypothermia be protective. 00:10:30.528 --> 00:10:34.298 A lot of people have done animal research that is more mirrors 00:10:34.298 --> 00:10:37.878 this cardiac arrest situation that has shown that, that you can... 00:10:37.908 --> 00:10:40.738 This is really one of the best ways to protect the brain. 00:10:41.088 --> 00:10:44.268 And part of that, we think, is because when, you know, we talk about these 00:10:44.268 --> 00:10:48.548 cells deciding to die, there's a lot of ways they can decide to die. 00:10:48.928 --> 00:10:52.558 And you could think, "Oh, I can get a drug that blocks one of those ways." 00:10:53.308 --> 00:10:56.128 But then the, then the, you know, the cell just goes around, you know, 00:10:56.128 --> 00:10:59.958 basically goes around the corner and takes a different pathway to dying. 00:11:00.238 --> 00:11:04.248 Um, dissimilar from cancer, where it may be like- Right this is the specific 00:11:04.398 --> 00:11:08.698 thing, and if I block that or, you know, a, a sort of monogenetic, you 00:11:08.698 --> 00:11:12.128 know, neurologic disease where you're like, "If I can stop the body from, 00:11:12.368 --> 00:11:16.518 from making that one bad protein, I can, I can stop the disease here." 00:11:16.548 --> 00:11:18.348 But there's lots of ways that the brain dies. 00:11:18.688 --> 00:11:21.768 So the th- th- the thought is that hypothermia maybe slows 00:11:21.768 --> 00:11:24.118 down multiple mechanisms. 00:11:24.458 --> 00:11:26.888 And, you know, that's, that's borne out in the animal data, but 00:11:26.888 --> 00:11:31.978 to some degree, we don't really know how to implement it people. 00:11:32.118 --> 00:11:33.738 Like, who are the people we should cool? 00:11:34.388 --> 00:11:37.008 You don't wanna cool people who aren't very injured because then you're 00:11:37.008 --> 00:11:40.618 exposing them to more time in the ICU and on sedatives and all this stuff. 00:11:41.408 --> 00:11:43.418 on the other hand, don't wanna... 00:11:43.478 --> 00:11:47.808 If you can protect somebody, you wanna cool them long enough so that 00:11:48.628 --> 00:11:52.518 You're giving that brain a chance to, to get as much recovery as it can. 00:11:54.088 --> 00:11:56.908 so they, they did some studies back in two thousand that were, were 00:11:56.908 --> 00:12:00.318 relatively small studies called the Haka study and the Bernard study, 00:12:00.788 --> 00:12:05.948 but they did have pretty eye-popping results of improving mortality. 00:12:06.408 --> 00:12:08.808 Um, they didn't use modern devices. 00:12:08.808 --> 00:12:12.408 They more or less used ice packs and, and cooling, cooling, cooling 00:12:12.408 --> 00:12:14.518 blankets, fans, things like that. 00:12:15.008 --> 00:12:18.438 But they also, in their control groups, didn't do much to control fever. 00:12:18.438 --> 00:12:24.398 So that was one of the criticisms of those studies in that the effect they saw from 00:12:24.398 --> 00:12:30.038 hypothermia more this protection from being low, was it the fact that being a 00:12:30.038 --> 00:12:32.978 little low was a good way to not go high? 00:12:33.418 --> 00:12:37.578 So that, that left-- even though the guidelines, um, that came to be after, 00:12:37.678 --> 00:12:43.028 after two thousand and two when those studies came out were favorable and 00:12:43.028 --> 00:12:48.118 saying that we should cool people for roughly twelve to twenty-four hours, 00:12:48.388 --> 00:12:52.618 there, there were these unanswered questions as to would this really work 00:12:52.618 --> 00:12:58.788 in, in a, you know, bigger population th- and also a population where the 00:12:58.788 --> 00:13:02.588 ICU was, was more diligently treating fever in a, in a control group. 00:13:03.270 --> 00:13:03.390 Scott: Yeah. 00:13:04.170 --> 00:13:04.540 Okay. 00:13:04.540 --> 00:13:09.920 So, so walking into this, the design of this trial and, and the, 00:13:09.990 --> 00:13:13.220 the design process of this trial was, it was extended, getting 00:13:13.220 --> 00:13:14.400 funding and various things. 00:13:15.000 --> 00:13:20.400 Uh, it's thought that hypothermic cooling of patients that come in after cardiac 00:13:20.400 --> 00:13:25.650 arrest, restoration of, of, uh, of the heart, of, of blood flow, they come 00:13:25.650 --> 00:13:31.830 in, does cooling them, it-- uh, it's thought that cooling is beneficial. 00:13:32.210 --> 00:13:34.440 There still remains a number of questions. 00:13:34.490 --> 00:13:38.340 Conclusive evidence of benefit is also not there. 00:13:38.660 --> 00:13:44.160 So going into this trial, it is somewhat standard of care at your University 00:13:44.160 --> 00:13:48.420 of Michigan Hospital that if somebody suffers from this, they will be cooled. 00:13:49.130 --> 00:13:53.570 So what is it that ICECAP decides to explore? 00:13:53.570 --> 00:13:55.280 I imagine it could be temperature. 00:13:55.670 --> 00:13:58.890 I could imagine how fast you get them there, whether you cool them 00:13:58.890 --> 00:14:02.720 at all, whether you just prevent this, how long you cool them. 00:14:02.970 --> 00:14:05.520 What is it that ICECAP is going to explore? 00:14:06.638 --> 00:14:07.008 Will Meurer: Yeah. 00:14:07.108 --> 00:14:09.008 I think one other thing that, that maybe I 00:14:09.010 --> 00:14:09.270 Scott: Hmm. 00:14:09.468 --> 00:14:14.068 Will Meurer: out about those early studies is one thing that they did was they 00:14:14.068 --> 00:14:19.558 focused on sort of the patients who they thought had the best chance of recovery, 00:14:19.788 --> 00:14:25.108 and these were people they thought had a cardiac arrest from cardiac causes. 00:14:25.548 --> 00:14:29.738 And that meant when, when EMS shows up, they're in this ventricular fibrillation 00:14:29.738 --> 00:14:33.808 or v-ventricular tachycardia-type rhythm, like my guy at the VA. 00:14:34.288 --> 00:14:38.168 Um, they get shocked, and their, their heart gets restored. 00:14:38.498 --> 00:14:42.108 So that's sort of one mechanism why the, why the heart starts or 00:14:42.138 --> 00:14:46.503 h- why the heart stops And that's thought to be favorable because you 00:14:46.503 --> 00:14:48.573 basically you're like a normal person. 00:14:48.573 --> 00:14:50.583 You don't know you have any medical problems. 00:14:50.883 --> 00:14:53.083 And all of a sudden, a clot flicks off to a big vessel in 00:14:53.083 --> 00:14:55.193 your coronary and bam, you drop. 00:14:55.513 --> 00:14:58.763 So your body isn't very sick from other diseases, maybe a little bit 00:14:58.763 --> 00:14:59.953 of hypertension here and there. 00:15:00.363 --> 00:15:04.883 But, you know, getting that person, you know, back and going is one thing. 00:15:05.313 --> 00:15:09.483 The other type of cardiac arrest where somebody's heart stops is 00:15:09.483 --> 00:15:10.943 what we call non-shockable arrest. 00:15:11.003 --> 00:15:15.293 And that comes from else going on with the patient. 00:15:15.363 --> 00:15:20.433 Like they have a bad respiratory problem and they get less and less oxygen. 00:15:20.433 --> 00:15:23.163 And all of a sudden, there's not enough oxygen in their bloodstream 00:15:23.483 --> 00:15:28.483 to keep the heart moving or they have a blood clot heaven forbid. 00:15:28.483 --> 00:15:31.993 And this is something that we will find came up more commonly than we thought. 00:15:32.483 --> 00:15:34.823 They take an overdose and they stop breathing. 00:15:34.853 --> 00:15:40.323 And when they stop breathing, the body is more slowly being deprived of oxygen. 00:15:40.363 --> 00:15:45.853 Whereas in that initial case of the sudden drop, you have a normal oxygen level. 00:15:45.853 --> 00:15:51.613 So even though your heart has stopped, there was a fair bit of oxygen and 00:15:51.613 --> 00:15:53.123 stuff that was pushed up to the brain. 00:15:53.433 --> 00:15:57.493 Whereas if you're not breathing for a while and a while and a while, 00:15:57.863 --> 00:15:59.803 there's even more sort of pre-injury. 00:16:00.043 --> 00:16:02.423 So when I said we don't really know much about severity, 00:16:02.773 --> 00:16:04.263 we did know that one thing. 00:16:04.553 --> 00:16:09.323 And the one limitation of the trials was those 2002 trials, they 00:16:09.323 --> 00:16:12.053 didn't think those people with the latter type, the non-shockable, 00:16:12.323 --> 00:16:14.333 had a lot of prospect for recovery. 00:16:14.583 --> 00:16:17.373 So they really only studied those who had shockable rhythms. 00:16:17.583 --> 00:16:21.363 So another thing that another big question we had is the guidelines 00:16:21.363 --> 00:16:24.153 were vague the non-shockable people. 00:16:24.183 --> 00:16:29.563 They said, please cool the people who had shockable rhythms, but the people with 00:16:29.563 --> 00:16:32.233 non-shockable rhythms, we're not sure. 00:16:32.653 --> 00:16:36.473 There's no reason to think that the brain wouldn't potentially be 00:16:36.473 --> 00:16:40.343 protected from hypothermia based on these two different mechanisms. 00:16:40.663 --> 00:16:45.073 But there was a worry that maybe these people had such a bad prognosis that if 00:16:45.073 --> 00:16:48.213 you include too many people like that in your trials, you're not going to have 00:16:48.213 --> 00:16:50.033 enough good outcomes to see a difference. 00:16:51.115 --> 00:16:55.895 Scott: Okay, so the, the, the reason for the cardiac arrest, shock, um, 00:16:55.895 --> 00:16:57.955 shockable and non-shockable is a question. 00:16:58.585 --> 00:17:02.445 Um, and then largely hypothermia. 00:17:02.715 --> 00:17:06.855 This trial-- By the way, I, I, I'm not sure we, we laid this out. 00:17:07.355 --> 00:17:11.935 When you and I are speaking right now, this trial is over, um, 00:17:11.935 --> 00:17:13.355 that we, we know the results. 00:17:13.355 --> 00:17:15.095 We are not gonna talk about the results. 00:17:15.095 --> 00:17:16.455 The results are coming out. 00:17:16.825 --> 00:17:21.835 Uh, believe they've been accepted into JAMA, but, um, that we're 00:17:21.835 --> 00:17:25.415 going to have another podcast of the results, and we're gonna talk 00:17:25.415 --> 00:17:26.805 about the results and what they mean. 00:17:27.245 --> 00:17:30.775 We wanna talk about the design, so we're setting up the design part of this. 00:17:31.215 --> 00:17:35.865 So what is it y- So you, you are going to look at two different kinds of 00:17:35.865 --> 00:17:37.995 patients, shockable and non-shockable. 00:17:38.475 --> 00:17:42.845 What is it-- What are the interventions you're assigning to a patient? 00:17:44.508 --> 00:17:49.388 Will Meurer: I think one of the things is, we arrived at this after 00:17:49.388 --> 00:17:52.968 having these meetings as part of this interesting and, and really cool 00:17:52.968 --> 00:17:56.948 regulatory science initiative that was sponsored by the US Food and Drug 00:17:56.948 --> 00:18:03.228 Administration and the, the US, uh, and the Office of the Director at the NIH. 00:18:03.708 --> 00:18:06.428 Um, we did this project called ADAPTT, which is, which is where we 00:18:06.428 --> 00:18:07.978 s- we, we started to work together. 00:18:08.408 --> 00:18:15.478 And, um, in the, the process, the, the sort of straw man design for 00:18:15.478 --> 00:18:19.028 something like ICECAP was to look at a, a, a few different cooling 00:18:19.028 --> 00:18:24.698 durations like twelve, twenty-four, and forty-eight in shockable rhythms only. 00:18:25.518 --> 00:18:29.558 we had more feedback from a variety of stakeholders who were at these 00:18:29.558 --> 00:18:33.508 meetings, it became clear that, that that was probably too narrow. 00:18:33.508 --> 00:18:37.258 There was so much uncertainty in the non-shockable people, but a, 00:18:37.328 --> 00:18:41.858 a great unmet need that we should work to try to study both of those 00:18:41.858 --> 00:18:43.478 populations at the same time. 00:18:44.338 --> 00:18:48.838 But as we emerged in terms of, you know, how we were planning the trial 00:18:48.838 --> 00:18:55.218 and what decisions we're making, we, um, to make sure that if there was a signal 00:18:56.108 --> 00:19:01.098 the shockable rhythms, that we could sort of find that even if things were 00:19:01.458 --> 00:19:03.188 different in the non-shockable rhythms. 00:19:03.488 --> 00:19:07.428 Or similarly, if because the non-shockables typically have 00:19:07.428 --> 00:19:10.128 more brain damage, maybe they need to be cooled longer. 00:19:10.448 --> 00:19:13.678 So th-those were, those were some of the things that, that came through. 00:19:14.358 --> 00:19:17.858 We really wanted-- We didn't wanna study how cold you made them. 00:19:17.858 --> 00:19:21.978 We, we focused on thirty-three degrees or roughly ninety Fahrenheit from the 00:19:21.978 --> 00:19:26.038 animal models, that was, that was sort of the best-- that was a sort of sweet spot. 00:19:26.328 --> 00:19:29.738 Some people have looked at other, you know, like thirty-four or thirty-six. 00:19:30.148 --> 00:19:34.368 And we, we, we based on our read of the, the human and animal literature, 00:19:34.678 --> 00:19:36.678 looking at depth wasn't so interesting. 00:19:37.698 --> 00:19:42.223 duration we felt was most interesting like I said, in the 00:19:42.223 --> 00:19:44.533 neonates, it was about 72 hours. 00:19:44.813 --> 00:19:48.413 There was a very encouraging study in pediatrics, which didn't quite achieve 00:19:48.443 --> 00:19:53.493 statistical significance called BABKA, but 48 hours of cooling in, you know, 00:19:53.493 --> 00:19:58.633 kids who are 18 and under, most of whom were actually two and under, 48 hours 00:19:58.633 --> 00:20:02.213 of cooling was, was quite promising in terms of improving survival. 00:20:03.143 --> 00:20:05.063 So there were those sorts of numbers. 00:20:05.333 --> 00:20:08.243 But then in that one of those first Australian studies, they got 00:20:08.243 --> 00:20:11.123 people cooled really quick, and they only cooled them for 12 hours, 00:20:11.163 --> 00:20:12.683 and they also saw great results. 00:20:12.943 --> 00:20:15.523 So we had this sort of range of uncertainty. 00:20:17.263 --> 00:20:19.643 So duration was important. 00:20:20.123 --> 00:20:22.683 But another thing that was crucially important to us 00:20:22.993 --> 00:20:24.443 was the therapeutic window. 00:20:25.663 --> 00:20:29.153 we really felt that based on the preclinical data, that it was 00:20:29.153 --> 00:20:31.733 important to get people cooled quickly. 00:20:32.583 --> 00:20:36.553 Some people come in cold, you know, obviously, you've spent a lot of 00:20:36.553 --> 00:20:40.573 your life up in Minnesota, easier to be-- easier for a patient to get 00:20:40.573 --> 00:20:44.633 cold up in Minnesota in the winter than it is in Austin in the summer. 00:20:45.073 --> 00:20:48.613 So there is some of that, but a lot of it is really, if the body's 00:20:48.713 --> 00:20:53.743 brain is injured, it, turns off your temperature center to some degree. 00:20:53.983 --> 00:20:57.303 So your body is sort of even in a relatively warm environment, 00:20:57.943 --> 00:20:59.433 body is going to get cold. 00:20:59.433 --> 00:21:05.663 So people cold early something we looked at as very important to reduce 00:21:05.663 --> 00:21:07.313 variability in the trial, right? 00:21:07.313 --> 00:21:10.053 Because if we're like, we're testing these different durations, 00:21:10.053 --> 00:21:13.323 but some people are getting cooled starting 12 hours after injury. 00:21:13.663 --> 00:21:17.403 Some people it's two hours after injury, some people it's six hours after injury. 00:21:17.783 --> 00:21:20.263 We felt that that could-- that heterogeneity could, 00:21:20.683 --> 00:21:22.133 could really sink our trial. 00:21:22.493 --> 00:21:26.873 So we did have a focus on with the hopes that, that sites would get 00:21:26.873 --> 00:21:33.233 really engaged and get devices on people quickly to have, um, cooled 00:21:33.233 --> 00:21:35.173 quickly as a condition of the trial. 00:21:35.913 --> 00:21:39.153 Because of that, and because the guidelines at the time it were-- was 00:21:39.153 --> 00:21:46.223 designed were cool everyone, we couldn't have what one would consider a classic 00:21:46.273 --> 00:21:50.493 control group, um, in terms of let's just turn-- let's just put a device 00:21:50.493 --> 00:21:54.443 on and set it to 37 degrees, you know, ninety-eight point six, and just make 00:21:54.443 --> 00:21:56.483 sure they don't get fever, you know. 00:21:56.483 --> 00:21:59.833 So that-- we couldn't do that because we requi-- we wanted people to be 00:21:59.833 --> 00:22:04.323 cooled before they were even to be eligible for the trial so that, that 00:22:04.323 --> 00:22:07.273 sites-- since sites were cooling everybody as a condition of being in 00:22:07.273 --> 00:22:11.373 the study, at least anybody with a coma or that had to be their usual 00:22:11.373 --> 00:22:17.183 practice to get into the study, that meant we could require patients to be 00:22:17.183 --> 00:22:20.873 cooled to a certain amount before they could be randomized to a duration. 00:22:22.335 --> 00:22:22.565 Scott: Okay. 00:22:22.805 --> 00:22:27.965 So we are in the ICECAP trial, we're gonna randomize people to a duration, 00:22:28.025 --> 00:22:33.555 and a critical part of all of this is that we can't do no duration, no cooling. 00:22:33.935 --> 00:22:38.365 Uh, you would slow down people that are gonna be cooled by trying to get consent 00:22:38.365 --> 00:22:40.255 or a waiver of consent or all of that. 00:22:40.475 --> 00:22:42.075 Standard of care is to cool them. 00:22:42.075 --> 00:22:46.605 So everybody is cooled in the trial, but you're going to vary 00:22:46.605 --> 00:22:51.445 the length of time they're cooled in the trial, um, uh, within this. 00:22:51.775 --> 00:22:57.145 And initially, uh, a- and, and going back to this-- By the way, the ADAPT-IT 00:22:57.145 --> 00:23:01.275 project that you mentioned was, was a fabulous project, and I think we had six 00:23:01.275 --> 00:23:07.405 different trials, and the goal of that project was to explore innovative designs 00:23:07.405 --> 00:23:13.715 being brought to clinical trials in the emergency room setting and to study 00:23:13.715 --> 00:23:16.495 barriers to bringing in innovative design. 00:23:17.165 --> 00:23:21.825 And, uh, interestingly, I think the number one barrier was statisticians, but that, 00:23:21.945 --> 00:23:24.055 that's a, a topic for a different day. 00:23:24.315 --> 00:23:29.315 Um, uh, and this-- there, there was, there was research, and we, we had, 00:23:29.315 --> 00:23:34.265 uh, IRB approval to study the people building the designs as to, to what 00:23:34.265 --> 00:23:38.700 were barriers and what were going on So I remember the initial design 00:23:38.700 --> 00:23:45.100 that I simulated for this trial was randomizing patients to twelve hours, 00:23:45.100 --> 00:23:47.350 twenty-four hours, and forty-eight hours. 00:23:47.590 --> 00:23:50.120 And initially, it wasn't the two populations, so we'll 00:23:50.120 --> 00:23:51.510 kind of ignore that part. 00:23:52.000 --> 00:23:57.970 And, uh, we had a dichotomous outcome of their ninety-day MRS status, and we 00:23:57.970 --> 00:24:03.240 simulated those trials and showed a number of those results, and a lot of times 00:24:03.240 --> 00:24:04.970 it didn't really answer the questions. 00:24:04.970 --> 00:24:08.110 There was a great deal of, "Wow, boy, I wish we had more on the 00:24:08.110 --> 00:24:09.660 smaller ones in this case." 00:24:09.660 --> 00:24:15.290 Is even somewhat of an optimal curve that it kind of goes up at twenty-four 00:24:15.290 --> 00:24:19.940 and kind of comes down, left huge uncertainty whether this was flat, 00:24:19.940 --> 00:24:22.660 whether what the shape of this curve was. 00:24:22.660 --> 00:24:30.210 So there was a desire to have more durations, focusing patients where the 00:24:30.210 --> 00:24:33.360 best benefit was being, being seen. 00:24:33.700 --> 00:24:38.740 And so as you described, the next generation of this trial was, first 00:24:38.740 --> 00:24:42.770 of all, changing the endpoint to analyzing the whole scale, and 00:24:42.770 --> 00:24:44.220 we'll get to how we did that. 00:24:44.830 --> 00:24:50.670 But we opened up six hours, twelve hours, eighteen hours, twenty-four hours, 00:24:50.940 --> 00:24:55.660 all the way up, I think, originally to eighty-four and ninety-six hours. 00:24:56.120 --> 00:25:00.290 There were twelve different durations that a patient could be randomized 00:25:00.530 --> 00:25:05.780 in version number two of this trial that we started to simulate. 00:25:08.988 --> 00:25:12.328 Will Meurer: And yeah, and then I think this was one of the really great things 00:25:12.328 --> 00:25:18.598 about the Adaptive project was that by sort of illustrating design first, you 00:25:18.598 --> 00:25:22.318 could show people like Oh, I don't know. 00:25:22.318 --> 00:25:25.938 At the end of that trial, I'm gonna be sad or have this anticipated 00:25:25.938 --> 00:25:27.428 regret as we, we talk about it. 00:25:27.458 --> 00:25:29.288 Or, or doing the pre-mortem, right? 00:25:29.318 --> 00:25:32.898 If we do that twelve, twenty-four, forty-eight trial and it's, it's, it's 00:25:32.898 --> 00:25:37.888 sort of like, "Oh, we should have gone out to seventy-two," or, "Oh, maybe, 00:25:37.888 --> 00:25:39.308 maybe six would've been better." 00:25:39.338 --> 00:25:43.088 Or so, so, so that-- You know, I think that's an important concept. 00:25:43.118 --> 00:25:50.558 I think the thing that also is, you know, I think really fascinating is that, you 00:25:50.558 --> 00:25:55.098 know, by seeing the way the trial could come out, then you get people together 00:25:55.098 --> 00:25:58.678 and they're like, "Gosh, we need to, we need to do something a little different." 00:25:59.358 --> 00:26:02.148 And the other thing, though, is you do have to put this-- And, and 00:26:02.148 --> 00:26:05.468 sometimes I think, again, when you say like statisticians are the, are 00:26:05.468 --> 00:26:10.328 the barrier, you, you're also working with, hey, the guidelines say cool 00:26:10.328 --> 00:26:11.978 everybody for twenty-four hours. 00:26:12.298 --> 00:26:16.378 So to some degree you could say, yeah, let's look from ninety-six to zero. 00:26:17.398 --> 00:26:21.438 from a statistical perspective, you know, the most efficient way to, to do that 00:26:21.438 --> 00:26:24.468 is you're gonna start putting people on both ends to sort of see like, oh, 00:26:24.468 --> 00:26:28.378 is this, i-is this possibly flat or, or maybe there's gonna be an upslope in the 00:26:28.378 --> 00:26:32.628 middle, but, but, but, you know, kind of go into the ends and, and fill in. 00:26:32.948 --> 00:26:36.158 But since those are far from, you know, both those are far from what was 00:26:36.158 --> 00:26:40.528 guideline recommended at the time, the human constraint on the model was like, 00:26:40.988 --> 00:26:44.918 we do have to do it this way because it, it's not ethical to all of a sudden 00:26:45.558 --> 00:26:47.138 cool people for ninety-six hours. 00:26:47.168 --> 00:26:50.788 Um, you know, people who are in ICUs, you're gonna-- You know, if 00:26:50.788 --> 00:26:53.358 they start to wake up, you're gonna want them to let, let them wake up. 00:26:53.418 --> 00:26:54.118 So, so the, the... 00:26:54.118 --> 00:26:58.238 You know, if it's only six hours of cooling, the guidelines say twenty-four. 00:26:58.238 --> 00:27:00.268 Patients are gonna be like, "Why are you putting my family 00:27:00.268 --> 00:27:01.678 member on such a small duration?" 00:27:01.978 --> 00:27:06.068 So, so we did have this constraint because there was, you know, real 00:27:06.318 --> 00:27:09.208 recommendations for practice that we... 00:27:09.358 --> 00:27:11.528 You know, I think in retrospect sometimes people say, "Well, 00:27:11.528 --> 00:27:15.578 like, why didn't you just evenly distribute them across ten arms?" 00:27:15.948 --> 00:27:17.438 And it's like, wasn't... 00:27:17.438 --> 00:27:20.448 You know, based on what we knew about the science at the time we were coming up with 00:27:20.448 --> 00:27:24.188 the design and starting the trial, you know, that wouldn't have been ethical. 00:27:24.248 --> 00:27:27.278 So that, so that's I think, you know, important, and I think 00:27:27.278 --> 00:27:28.228 that was one of the things. 00:27:28.828 --> 00:27:30.978 You know, you would show us a d- 00:27:31.135 --> 00:27:35.135 Scott: Yep. 00:27:35.138 --> 00:27:37.928 Will Meurer: a little too, too long on this neutral case. 00:27:37.928 --> 00:27:39.828 Like, why is it, why is it putting people over there?" 00:27:39.828 --> 00:27:44.678 And then you'd say, because it wants to know, and that's how it's 00:27:44.678 --> 00:27:46.208 gonna find that slope of that line." 00:27:46.208 --> 00:27:49.578 And say, "Well, like, let's, let's, let's, let's see if we can, you know, 00:27:49.688 --> 00:27:51.398 nudge that backwards so that it's... 00:27:51.768 --> 00:27:56.308 It needs to have stronger evidence that there's an upslope, you know, between, you 00:27:56.308 --> 00:27:59.458 know, durations that we've used before, twelve to forty-eight, before it starts 00:27:59.458 --> 00:28:01.068 looking at those longer durations." 00:28:01.068 --> 00:28:03.978 So I think that was so crucially important. 00:28:03.978 --> 00:28:06.518 It took a lot of, you know, time and energy to go back 00:28:06.518 --> 00:28:07.768 and, and think of those things. 00:28:08.238 --> 00:28:11.898 But, you know, it's one of those things, though, when people look 00:28:11.898 --> 00:28:15.998 back at the design, sometimes they're like, "Hey, why did they do that?" 00:28:16.108 --> 00:28:19.738 But once you know the results- Like, the reason we were doing the trial 00:28:19.738 --> 00:28:20.888 was we didn't know the results. 00:28:20.888 --> 00:28:22.318 We didn't know what this was gonna look like. 00:28:23.048 --> 00:28:28.298 Um, so we wanted it to be flexible to a variety of different truths and be able 00:28:28.298 --> 00:28:33.158 to get us, uh, an answer that could be very useful to us under a variety of these 00:28:33.158 --> 00:28:40.998 scenarios, whether it was like up sloping late, up sloping early, flat, going down. 00:28:40.998 --> 00:28:43.908 And I think that was something that, that when people say, "Well, what-- 00:28:44.278 --> 00:28:46.228 why'd you do all this complicated stuff?" 00:28:46.688 --> 00:28:49.028 You know, this is something that's come up in adaptive designs. 00:28:49.028 --> 00:28:52.658 I think like the ASTON trial of the neutrophil inhibitor for stroke, 00:28:53.108 --> 00:28:54.558 I think is, is sometimes cited. 00:28:54.598 --> 00:28:56.388 It was a really innovative design. 00:28:56.438 --> 00:29:00.738 They, they went through so many different dose tiers in their design, and I 00:29:00.738 --> 00:29:02.368 thought it was like an amazing trial. 00:29:02.368 --> 00:29:07.128 But then critics later are like, they could have learned that with three doses 00:29:07.128 --> 00:29:08.758 and, you know, a third of the patients." 00:29:09.208 --> 00:29:11.868 But didn't know that in advance, right? 00:29:11.868 --> 00:29:15.498 Like, if they had done three doses, maybe they would have tested 00:29:15.498 --> 00:29:18.418 five-- you know, three different ones after that initial trial. 00:29:18.708 --> 00:29:22.968 As opposed to they got to a very convincing answer that in, in 00:29:22.968 --> 00:29:27.088 the population they were testing, their agent, you know, didn't, 00:29:27.118 --> 00:29:28.818 didn't help those stroke patients. 00:29:28.818 --> 00:29:32.888 So, so I think sometimes when we have adaptive designs that, that 00:29:33.038 --> 00:29:37.128 kind of go more into that, neutral space, people are, people are like... 00:29:37.228 --> 00:29:41.098 Or even adaptive designs that show something positive, people are like, "Oh, 00:29:41.428 --> 00:29:45.598 well, it would've been much easier to just assign them to those two groups," right? 00:29:45.598 --> 00:29:46.078 But it's like, 00:29:46.825 --> 00:29:47.045 Scott: Right, right, 00:29:47.148 --> 00:29:48.098 Will Meurer: that when we started. 00:29:48.505 --> 00:29:48.595 Scott: right. 00:29:48.595 --> 00:29:48.725 Right. 00:29:49.155 --> 00:29:49.375 Right, right. 00:29:49.785 --> 00:29:50.115 Okay. 00:29:50.315 --> 00:29:54.835 So i- through the simulations, a- as you describe this, quickly, by the 00:29:54.835 --> 00:29:59.605 way, 84 and 96 hours dropped out, largely for operational things, that 00:29:59.605 --> 00:30:03.275 people are in the, for five days in the, the, the emergency room, and 00:30:03.275 --> 00:30:06.565 it would've been awkward to do the trial where they go to the ICU as... 00:30:06.845 --> 00:30:11.825 So we dropped those off, and we-- I, I remember showing a simulation where 00:30:11.825 --> 00:30:18.495 initially we simulate to those same three arms, 12, 24, and 48, and then 00:30:18.495 --> 00:30:21.105 we do response adaptive randomization. 00:30:21.485 --> 00:30:26.805 We allocate patients where they're most likely to be benefit across that curve. 00:30:26.855 --> 00:30:31.615 If the low doses are doing the best, we put more there, refining that later ones. 00:30:31.965 --> 00:30:36.265 And I showed an example, a single trial where the curve went up, it 00:30:36.265 --> 00:30:39.595 was flat, it went down a little bit, but then it started to go back up. 00:30:39.625 --> 00:30:43.705 I was using a smoothing spline across the, the 12 durations. 00:30:44.325 --> 00:30:47.555 And it started to assign patients at 72 hours. 00:30:48.205 --> 00:30:54.475 And the clinicians all said, "Nope, we would never do that," that that, that 00:30:54.475 --> 00:30:57.035 dose response curve is not believable. 00:30:57.395 --> 00:31:03.455 There's the-- It's, it's not conceivable that the curve across durations would 00:31:03.455 --> 00:31:07.665 start to decline, that patients do worse as you cool them more, and all 00:31:07.665 --> 00:31:09.595 of a sudden it starts to go up again. 00:31:10.265 --> 00:31:14.615 And that was a, that was a, a, a really important insight. 00:31:14.955 --> 00:31:21.995 Also, uh, on the, on the other side, largely it was that this curve is gonna be 00:31:21.995 --> 00:31:28.215 an inverted U, that if this is beneficial, or if it's not beneficial, it fits on 00:31:28.215 --> 00:31:32.315 this curve, that there's gonna be a point where cooling more is beneficial. 00:31:32.685 --> 00:31:36.875 It may then be flat for some length of time, and then it's gonna go down. 00:31:36.875 --> 00:31:39.065 And we know at the extremes those would be the cases. 00:31:39.065 --> 00:31:43.225 If you cool somebody for 30 days, they're not going to do well, and, 00:31:43.225 --> 00:31:44.755 and we know that it's gonna get worse. 00:31:45.255 --> 00:31:49.605 Now, so that became the analysis model of this trial, that it's 00:31:49.605 --> 00:31:51.825 an inverted U dose response. 00:31:51.825 --> 00:31:53.555 It has a-- it can have a flat area. 00:31:53.925 --> 00:31:59.585 The important part is all of the, the, the 10 doses could be on the upslope. 00:32:00.555 --> 00:32:04.565 So we modeled it so the doses are somewhere on that inverted U. 00:32:04.565 --> 00:32:07.935 They could all be on the upslope, and 72 hours is the best. 00:32:08.455 --> 00:32:11.445 They could all be on the downslope, and cooling is bad. 00:32:11.735 --> 00:32:13.575 The more you cool them, the worse they get. 00:32:13.575 --> 00:32:17.525 They could all be flat, that from six to 72, it doesn't matter, it's flat. 00:32:17.555 --> 00:32:21.005 Or it could go up and be flat, it could be flat and go down. 00:32:21.495 --> 00:32:26.370 That's the model that drives the trial And what's really nice about that, 00:32:26.370 --> 00:32:30.880 so there's a Bayesian model of this inverted U th- that allows the doses 00:32:30.880 --> 00:32:33.180 to be ordered somewhere on that scale. 00:32:33.890 --> 00:32:39.260 And what we're looking for is the smallest dose that achieves the highest level, 00:32:39.780 --> 00:32:45.150 and that's defined by this, the, as this optimal dose that's defined by the curve. 00:32:45.510 --> 00:32:50.390 Because we know if it's getting flat, there's-- you don't wanna go bigger. 00:32:50.470 --> 00:32:51.860 There's no reason to go bigger. 00:32:51.860 --> 00:32:53.770 It's not gonna go flat and then up. 00:32:53.840 --> 00:32:54.990 It can't in this shape. 00:32:56.000 --> 00:33:01.020 So we use that in response-adaptive randomization to allocate patients, 00:33:01.550 --> 00:33:03.740 and that was the next version of this. 00:33:03.740 --> 00:33:08.180 And we added in, you, you addressed these gu- guardrails that we didn't 00:33:08.180 --> 00:33:12.000 wanna start with people on six hours, and we didn't wanna start 00:33:12.000 --> 00:33:15.440 with people on 60 hours or 72 hours. 00:33:15.940 --> 00:33:21.440 If the evidence was building that the dose response was continually increasing 00:33:21.440 --> 00:33:27.340 through up to 60, and the algorithm thought it was likely that was the best, 00:33:27.340 --> 00:33:33.930 we would open that arm with guardrails, and we would open six with guardrails if 00:33:33.980 --> 00:33:39.780 it appeared that six might be the most effective dose or this optimal dose. 00:33:39.780 --> 00:33:44.820 Like, if it looks really flat, we could open six, only with adaptive 00:33:44.820 --> 00:33:49.270 conditions in the trial, is how we started to migrate the design. 00:33:51.500 --> 00:33:52.180 Then... 00:33:52.210 --> 00:33:53.140 Yeah, yeah, go ahead. 00:33:53.208 --> 00:33:53.338 Will Meurer: no. 00:33:53.338 --> 00:33:54.358 No, no, you can, you keep 00:33:54.490 --> 00:34:00.550 Scott: I was gonna say, then it became we want to investigate both non-shockable 00:34:00.550 --> 00:34:05.890 and shockable, and the concern is that this optimal place is different 00:34:05.890 --> 00:34:07.910 for shockable and non-shockable. 00:34:07.910 --> 00:34:12.550 As you set up, it might be, depending on the etiology for why the person 00:34:12.550 --> 00:34:16.530 went down, you might wanna cool longer or shorter within that. 00:34:16.880 --> 00:34:22.670 So we ended up moving the design to having the same duration response 00:34:22.670 --> 00:34:27.170 model modeled separately in the two populations and having different 00:34:27.170 --> 00:34:32.380 response adaptive randomization probabilities by rhythm type. 00:34:35.858 --> 00:34:38.018 Will Meurer: Yeah, the thing I was gonna say is, you know, 00:34:38.338 --> 00:34:39.408 that's another thing, right? 00:34:39.448 --> 00:34:42.168 People, you know, would say, "We don't think this duration 00:34:42.168 --> 00:34:43.888 response can go up and down." 00:34:44.638 --> 00:34:48.658 But somebody later might, like, do some animal research and say, "Oh, 00:34:48.658 --> 00:34:54.078 gosh, biologically, you need to cool during this reperfusion period, and 00:34:54.078 --> 00:34:57.998 then maybe you need to cool later during this, you know, period where 00:34:57.998 --> 00:34:59.598 the brain is getting swollen." 00:35:00.598 --> 00:35:03.958 But again, that's not one of the arms we had, where it's like cool from 00:35:03.988 --> 00:35:08.418 six to twelve, pause, and then if you haven't woken up, cool again from, 00:35:08.418 --> 00:35:09.908 you know, seventy-two to ninety-six. 00:35:10.858 --> 00:35:14.338 One of the things that, that I sort of brought up, I think, back when we were 00:35:14.338 --> 00:35:18.778 having these planning meetings is, gosh, wouldn't it be nice if there was some 00:35:18.778 --> 00:35:20.698 way that we could tailor the treatment? 00:35:21.108 --> 00:35:24.038 You know, this is, this sort of Goldilocks approach to cooling. 00:35:24.388 --> 00:35:28.668 Like, if we had some way to measure the brain and, and, oh gosh, it's, it's 00:35:28.668 --> 00:35:30.598 crying out to us as we rewarm somebody. 00:35:30.638 --> 00:35:33.708 Let's, oh, oh, let's, let's like, then make them cool longer. 00:35:34.078 --> 00:35:40.008 And again, that was a lovely idea, but we as a scientific community at the time 00:35:40.238 --> 00:35:45.098 said, "Hey, Will, that's cute, but we don't know enough about how this works 00:35:45.098 --> 00:35:48.588 to do something that complicated that, that might take a billion patients." 00:35:48.918 --> 00:35:53.808 Um, but we have earnest uncertainty in these, you know, in these durations that 00:35:53.808 --> 00:35:57.828 we're testing and whether there's, know, I think, you know, as, as we'll get 00:35:57.828 --> 00:36:03.018 to next, while we don't have a control group, if everything's on the upslope, 00:36:03.698 --> 00:36:08.218 and it's a pretty good upslope, that's a, it's a pretty good way to connect the 00:36:08.218 --> 00:36:09.958 dots with a, with a no cooling group. 00:36:10.418 --> 00:36:13.578 Um, so, so I think have to make... 00:36:13.578 --> 00:36:18.178 You know, we did th-think that there could be individual designs that, that 00:36:18.208 --> 00:36:23.258 maybe could be better for patients, but we didn't have any of them off the 00:36:23.258 --> 00:36:28.228 shelf, and didn't have a good way to, to sort of think about how we could 00:36:28.228 --> 00:36:32.138 implement something like that, that sort of let me cool them until their 00:36:32.138 --> 00:36:34.328 brain tells me It's ready to wake 00:36:34.375 --> 00:36:35.305 Scott: We weren't ready. 00:36:35.645 --> 00:36:35.965 Yeah 00:36:36.068 --> 00:36:39.828 Will Meurer: we, you know, one of the other constraints that we all have in, 00:36:39.868 --> 00:36:44.388 in this space that is also something that's sort of really interesting is 00:36:45.288 --> 00:36:51.208 there is a lot of pressure in, in the US healthcare system in particular kind of 00:36:52.518 --> 00:36:57.108 get bored with providing critical care to somebody who might not wake up say, 00:36:57.788 --> 00:37:03.018 "Yeah, you know, Uncle Joe's lived a good life, but sure if he's gonna wake up." 00:37:03.018 --> 00:37:06.068 And then having people wanna do care limitations and remove people 00:37:06.068 --> 00:37:10.068 from technologic support which, which, which commonly happens. 00:37:10.438 --> 00:37:13.658 But in a trial like ICECAP, that's a huge problem, right? 00:37:13.658 --> 00:37:16.228 Because these people aren't being given an opportunity to wake up. 00:37:17.088 --> 00:37:18.478 of the potential mechanisms... 00:37:18.538 --> 00:37:21.908 You know, I talk about biological mechanisms of cooling. 00:37:23.158 --> 00:37:25.848 One of the potential mechanisms of cooling, at least in the clinical 00:37:25.848 --> 00:37:32.618 trial s-sense of potentially improving outcomes, is the longer you cool-- 00:37:32.618 --> 00:37:35.628 You can't, you can't pull the plug on somebody while they're cold. 00:37:35.628 --> 00:37:36.228 You have to, you know... 00:37:36.228 --> 00:37:40.578 So, so if you have a longer time period, you're basically, you know, 00:37:40.578 --> 00:37:45.128 sort of creating this sort of reverse shot clock of, you gotta wait at 00:37:45.128 --> 00:37:49.488 least this long before you, you take a shot at letting this person wake up. 00:37:49.968 --> 00:37:54.108 And in some of the trials that have been done, have been waking 00:37:54.108 --> 00:37:57.088 up, you know, twenty-two to thirty days after the injury. 00:37:57.558 --> 00:38:01.028 Now, that's not to say that every single patient who has a cardiac arrest should 00:38:01.028 --> 00:38:04.908 be given twenty-two to thirty days to wake up, but, but many of them aren't, 00:38:04.968 --> 00:38:07.178 aren't giving, being given more than two. 00:38:07.658 --> 00:38:12.338 And that's, again, that, that, you know, certain European countries, 00:38:12.338 --> 00:38:15.628 people are much more willing to give it a, give it a week or two. 00:38:16.048 --> 00:38:19.788 Um, again, not trying to make this a, a sort of value judgment on different 00:38:19.788 --> 00:38:23.388 societies, but it's an observation that, that people do handle these 00:38:23.388 --> 00:38:25.088 things a little differently in places. 00:38:25.568 --> 00:38:28.718 Um, and, and there's also a lot of clinicians who are like, 00:38:29.718 --> 00:38:31.048 "I'm sure they won't wake up." 00:38:31.998 --> 00:38:35.848 But if you tell that to everybody at day two, and sometimes it takes people five 00:38:35.848 --> 00:38:40.138 to twenty days to wake up, you're gonna be right, none of your patients wake up. 00:38:41.248 --> 00:38:43.498 But some of them would have if you had given them longer. 00:38:43.498 --> 00:38:44.348 So, so we also have 00:38:44.500 --> 00:38:44.640 Scott: And 00:38:44.688 --> 00:38:50.118 Will Meurer: of, you know, social element of the trial and, and working 00:38:50.118 --> 00:38:51.978 to do, you know, another intervention. 00:38:51.978 --> 00:38:55.128 You say, "Well, why did you, you, you pick duration?" 00:38:55.398 --> 00:38:56.728 'Cause that was most interesting. 00:38:57.008 --> 00:38:59.618 We tried to limit variability on this care limitation by 00:38:59.618 --> 00:39:01.048 having clinical standardization. 00:39:01.048 --> 00:39:04.298 Say, you know, "Please talk to us if you're doing this." 00:39:04.298 --> 00:39:08.758 You have to have a defined protocol to prognosticate whether you're doing an EEG, 00:39:08.758 --> 00:39:12.638 you're doing brain imaging, you're doing blood tests to make sure that if you, if 00:39:12.638 --> 00:39:16.138 you wanna tell a family that this person isn't gonna wake up, you do have some 00:39:16.138 --> 00:39:19.758 additional evidence that sort of backs that up, that it's, it's, A, it's pretty 00:39:19.758 --> 00:39:21.038 unlikely that they're gonna wake up. 00:39:21.038 --> 00:39:23.098 So that was another aspect of the trial. 00:39:23.098 --> 00:39:26.558 It was a feature of some concurrent European trials that, that went 00:39:26.558 --> 00:39:29.188 on, that they did, they did that in a standardized way. 00:39:29.528 --> 00:39:34.693 So that's another thing, but from a study design perspective people don't complete 00:39:34.693 --> 00:39:39.063 their duration of cooling because of early care limitations, it introduces, 00:39:39.103 --> 00:39:42.733 um, you know, noise into our trial. 00:39:42.733 --> 00:39:45.823 You know, our trial has less ability to pick up a treatment effect when those 00:39:45.823 --> 00:39:50.073 observations aren't contributing really to the, the treatment effect estimate. 00:39:51.540 --> 00:39:55.710 Scott: we, we, for, for especially the statisticians out 00:39:55.710 --> 00:39:57.420 there, we do intend to treat. 00:39:57.510 --> 00:40:02.580 So if a patient is, is g- is assigned forty-eight hours and dies at twelve 00:40:02.580 --> 00:40:05.710 hours, they're in the forty-eight-hour arm, and their outcome is that. 00:40:05.710 --> 00:40:08.840 If they somehow come off of it at twenty-four hours, 00:40:08.840 --> 00:40:09.800 they're forty-eight hours. 00:40:09.800 --> 00:40:12.600 So it's intent to treat, uh, from the arms of that. 00:40:12.600 --> 00:40:18.580 Um, I, I, yeah, I think it's an or-- in a really important part in the interactions 00:40:18.580 --> 00:40:25.200 of this, I remember we, we went to the NIH presenting to get this funded. 00:40:25.570 --> 00:40:28.430 I think there was discussion about... 00:40:28.530 --> 00:40:32.700 Sorry, at that time, we went with members of the FDA. 00:40:32.700 --> 00:40:37.230 The FDA really wanted this trial to run. 00:40:37.290 --> 00:40:41.440 Uh, Bram Zuckerman, in particular, really wanted this trial to run. 00:40:41.800 --> 00:40:47.160 Now, medical devices out there have been approved that they cool a patient. 00:40:48.390 --> 00:40:50.500 That's not tied to clinical benefit. 00:40:50.500 --> 00:40:54.260 It doesn't say it's good to cool people, but you've demonstrated you can cool 00:40:54.260 --> 00:40:59.135 somebody to thirty-three degrees And these are being used, and so there's 00:40:59.135 --> 00:41:03.395 not a great incentive for devices to run this trial, to fund this trial, 00:41:03.395 --> 00:41:05.055 so they're not gonna fund this trial. 00:41:05.275 --> 00:41:08.435 There might even be a disincentive to, to, to fund this trial. 00:41:09.025 --> 00:41:14.445 Um, the FDA wants this trial to run, and so we went to the NIH, and the 00:41:14.445 --> 00:41:19.025 FDA went, uh, on behalf of the design that we'd really like to see this 00:41:19.025 --> 00:41:24.415 trial run, which was sort of a unique experience, uh, uh, in, in the whole 00:41:24.415 --> 00:41:26.665 interactions of getting this trial run. 00:41:26.905 --> 00:41:31.235 And eventually this trial was, uh, funded by the NIH. 00:41:32.793 --> 00:41:33.253 Will Meurer: Yeah. 00:41:33.303 --> 00:41:39.803 I, I think the FDA even a little more excited so to, so to speak 00:41:39.803 --> 00:41:40.723 about it, because really the 00:41:40.755 --> 00:41:44.755 Scott: Yep. 00:41:46.093 --> 00:41:49.543 Will Meurer: So the use of them to-- You, you can set a different target, 00:41:49.883 --> 00:41:53.553 but really the idea was that they were to keep people at normal temperatures 00:41:53.843 --> 00:41:57.573 or pay-- or potentially warm people up who have environmental hypothermia. 00:41:57.933 --> 00:42:01.133 So to some degree-- Well, and, you know, every time I've given a presentation 00:42:01.133 --> 00:42:04.863 about ICECAP, I, I put in that disclosure, "I will discuss off-label 00:42:04.863 --> 00:42:09.113 uses of these devices," because, you know, the, the way that their label was. 00:42:09.283 --> 00:42:12.563 So the FDA felt that it was, uh, important from a regulatory science 00:42:12.563 --> 00:42:16.013 perspective to learn more about the safety of these devices when 00:42:16.013 --> 00:42:18.383 being used outside of their label. 00:42:18.713 --> 00:42:24.123 Um, so, so that was-- That, that gave them additional enthusiasm for our design. 00:42:24.123 --> 00:42:29.573 And you're right, it was really unique, I think, to have FDA I think 00:42:29.573 --> 00:42:31.003 FDA does a lot of great things. 00:42:31.053 --> 00:42:33.763 I think they can be great scientific partners, and I think in this case, 00:42:34.073 --> 00:42:35.433 this is a great example of that. 00:42:35.753 --> 00:42:39.163 Like, in that they were interested in doing what's right for patients, but, 00:42:39.503 --> 00:42:43.983 but learning in an unbiased way through a clinical trial where all the adverse 00:42:43.983 --> 00:42:47.523 events are being adjudicated, people are-- the outcome assessors are blinded 00:42:47.523 --> 00:42:51.663 to the duration of this cooling device that they were subjected to and so forth. 00:42:52.103 --> 00:42:54.643 So, so a lot of real positives. 00:42:54.643 --> 00:42:57.733 I mean, it was, it was, it, a delight working with them on it. 00:42:57.803 --> 00:43:00.833 And, you know, I, I was the sponsor of the IDE, so I've had, 00:43:01.173 --> 00:43:02.483 had great interactions with them. 00:43:02.483 --> 00:43:04.483 They're really, really thoughtful scientists there. 00:43:06.004 --> 00:43:11.464 Scott: Okay, so let's, let's summarize the design because, uh, uh, uh, our 00:43:11.464 --> 00:43:15.664 listeners are gonna tune into this, and then they're gonna tune into the results, 00:43:15.664 --> 00:43:17.464 and we'll do a podcast of the results. 00:43:17.464 --> 00:43:22.474 So this is a design of eighteen hundred patients combined across 00:43:22.474 --> 00:43:26.694 rhythm types, where initially the allocation is twelve, twenty-four, and 00:43:26.694 --> 00:43:29.214 forty-eight hours, equal randomization. 00:43:29.754 --> 00:43:33.354 After two hundred patients, an interim analysis is done. 00:43:34.124 --> 00:43:37.694 The Bayesian model is fit for both ris-- rhythm types. 00:43:38.064 --> 00:43:44.094 We do multiple imputation of patients with thirty days MRS status projecting 00:43:44.094 --> 00:43:50.480 to their ninety-day status We have 90-day MRS as the primary endpoint, and we use 00:43:50.480 --> 00:43:57.730 a weighted scale of the MRS for, for analyzing that, not a dichotomization 00:43:57.730 --> 00:43:59.450 of that, so a weighted scale. 00:44:00.300 --> 00:44:04.830 At the interim analysis, updated randomizations are made 00:44:04.830 --> 00:44:06.370 to the different durations. 00:44:07.570 --> 00:44:14.110 That is done every fifty patients in the trial that these-- the RAR is updated 00:44:14.540 --> 00:44:16.400 throughout the course of the trial. 00:44:17.050 --> 00:44:22.270 There's a possibility of opening up, uh, them on the right or the left. 00:44:22.270 --> 00:44:28.110 So the, the ones at the beginning, twelve to forty-eight are open and 00:44:28.110 --> 00:44:31.800 can be, and it can be allocated to right away, and anything in 00:44:31.800 --> 00:44:33.790 between that by every six hours. 00:44:34.230 --> 00:44:37.400 And certain conditions could open up six hours. 00:44:37.630 --> 00:44:41.800 We, of course, we talked about opening up zero, but that was not a possibility. 00:44:42.030 --> 00:44:43.970 So it could open up six. 00:44:43.970 --> 00:44:45.690 We talked about that in the design stage. 00:44:46.000 --> 00:44:49.160 And then it could open up sixty or seventy-two on the other end 00:44:49.160 --> 00:44:54.560 if this appears to be a continual increasing, um, uh, duration response. 00:44:55.410 --> 00:44:57.530 There is no early success. 00:44:57.580 --> 00:45:00.860 There's no stopping because we've determined the right answer. 00:45:01.140 --> 00:45:06.040 There is futility if there's, uh, comes to be at least a fifty percent 00:45:06.040 --> 00:45:10.850 probability that six hours is the best thing to do, we'll stop a rhythm type. 00:45:10.850 --> 00:45:12.230 And we, we call it futility. 00:45:12.230 --> 00:45:17.100 It's largely that there's reasonable evidence that there isn't an 00:45:17.100 --> 00:45:19.170 increasing duration response curve. 00:45:20.790 --> 00:45:27.500 The two primary analyses are this, are what is the optimal duration to cool that 00:45:27.500 --> 00:45:33.950 comes from the Bayesian model, and is there an increasing duration response? 00:45:34.060 --> 00:45:38.890 If there's an increasing duration response, if twelve is better than 00:45:38.890 --> 00:45:44.240 six and eighteen is better than twelve, it gives evidence without a 00:45:44.240 --> 00:45:47.180 zero arm that cooling is beneficial. 00:45:47.710 --> 00:45:53.400 And the FDA understood the non-non-zero arm, and they understood this as a, 00:45:53.480 --> 00:45:58.730 as a signal that cooling is beneficial to patients if there's an increasing 00:45:58.730 --> 00:46:00.530 relationship with length of cooling. 00:46:01.690 --> 00:46:05.770 Within that is part of the primary analysis, uh, in the 00:46:05.770 --> 00:46:08.080 trial and the two rhythm types. 00:46:08.420 --> 00:46:13.880 Have, have I, have I summarized the design appropriately? 00:46:14.513 --> 00:46:17.773 Will Meurer: Yeah, no, but we, we maybe take a brief little tangent 00:46:17.773 --> 00:46:19.633 into the, uh, weighted mRS. 00:46:19.663 --> 00:46:23.413 And I think, you know, others, you know, other, others have probably 00:46:23.413 --> 00:46:25.163 seen this in, in the stroke world. 00:46:25.590 --> 00:46:25.780 Scott: Yep. 00:46:26.333 --> 00:46:30.523 Will Meurer: for stroke, uh, we developed this weighting scale for, for ICECAP, 00:46:31.033 --> 00:46:34.973 um, a little earlier than the strokes-- the stroke one, m- m-- you know, emerged. 00:46:34.973 --> 00:46:39.183 In the stroke one, they, they talked to clinicians and, and patients and families 00:46:39.493 --> 00:46:42.853 to develop a series of we-- a series of weights for the, the mRS states. 00:46:43.323 --> 00:46:49.933 And, um, in, in, in pedia or in adult ICECAP, we, we set these sort 00:46:49.933 --> 00:46:54.083 of based on, on cl-- on what the clinicians thought with the goal of 00:46:54.182 --> 00:47:00.193 accomplishing two things Can we find people who more or less wake 00:47:00.193 --> 00:47:04.233 up, you know, their mRS is, is, is, you know, sort of better than four? 00:47:04.713 --> 00:47:08.133 And amongst those who wake up, can we distinguish amongst the people 00:47:08.133 --> 00:47:09.763 who have really excellent outcomes? 00:47:10.123 --> 00:47:16.112 I think when we commonly dichotomize, it's like you get full credit at a 0 full 00:47:16.152 --> 00:47:20.113 credit at a 1 full credit at a 2 and all of a sudden at a 3 you get no credit. 00:47:20.113 --> 00:47:21.483 It's the same as being dead. 00:47:21.973 --> 00:47:26.743 And that, in this disease, we felt was, was the possibility of 00:47:26.743 --> 00:47:28.123 showing important improvements. 00:47:28.433 --> 00:47:32.733 Because someone with an mRS of three, if they had a really severe stroke 00:47:32.783 --> 00:47:38.563 or severe stroke, had a ve- really severe cardiac arrest, at n- at, at 00:47:38.563 --> 00:47:41.033 three months, that might be a very good outcome, and they actually may have 00:47:41.033 --> 00:47:42.853 a, a potential for future trajectory. 00:47:43.153 --> 00:47:46.253 And we're doing a study called POST-ICECAP um, that we designed 00:47:46.253 --> 00:47:47.953 to actually live after ICECAP. 00:47:49.123 --> 00:47:52.583 initially, it was following patients after their three-month follow-up, but 00:47:52.583 --> 00:47:56.393 now it's following people at three, six, nine, and twelve months to look at 00:47:56.393 --> 00:47:58.023 that trajectory of recovery over time. 00:47:58.023 --> 00:48:02.163 And, and there are certainly patients for whom an mRS of three is, is, is 00:48:02.163 --> 00:48:06.693 a r- is a really, is a win in terms of their severity of, of, of injury. 00:48:06.693 --> 00:48:08.693 So, so we did design this weighted scale. 00:48:09.033 --> 00:48:12.403 It's very similar to the utility-weighted scale that is used, that was used in 00:48:12.403 --> 00:48:14.943 DAWN and DEFUSE and other stroke trials. 00:48:15.183 --> 00:48:19.153 Um, it's subtly different, but it, it, it's-- the, the concept is the 00:48:19.153 --> 00:48:22.733 same, even though we arrived at it for a scientific reason as opposed 00:48:22.733 --> 00:48:27.438 to inducing it from sort of Clinician and patient's, uh, preferences. 00:48:29.030 --> 00:48:32.170 Scott: just for disclosure of what it is, the MRS of zero, which is 00:48:32.170 --> 00:48:34.000 the best outcome, you get 10 points. 00:48:34.660 --> 00:48:36.340 A one, you get nine points. 00:48:36.390 --> 00:48:37.960 A two, you get eight points. 00:48:38.250 --> 00:48:40.110 A three, you get six points. 00:48:40.110 --> 00:48:43.070 So the two to three difference was considered greater. 00:48:43.400 --> 00:48:47.790 And then below three for four, five, and six, you get zero points, was, 00:48:47.790 --> 00:48:53.010 was, is the, the, the scale used, the weighting of that used in the trial. 00:48:55.090 --> 00:49:00.270 Okay, and, and we should, uh, highlight that MUSC and Sharon 00:49:00.270 --> 00:49:02.920 Yates did, uh, ran this trial. 00:49:03.220 --> 00:49:06.950 Uh, she's the-- they're the data coordinating center, did a tremendous 00:49:06.950 --> 00:49:10.520 job o-on this, um, in the trial. 00:49:10.550 --> 00:49:15.100 So a complex mult-- many interim analyses done during the trial, and they did a 00:49:15.100 --> 00:49:18.280 fantastic job, um, uh, running the trial. 00:49:18.800 --> 00:49:19.730 But we can't... 00:49:19.928 --> 00:49:22.528 Will Meurer: thing, like sometimes people are like, "Oh gosh, turning 00:49:22.528 --> 00:49:24.118 around an interim analysis to change your 00:49:24.330 --> 00:49:28.200 Scott: And... 00:49:28.238 --> 00:49:28.998 Will Meurer: a data freeze." 00:49:28.998 --> 00:49:32.118 And, and you know, they were-- they, they would, they would turn it around in a day 00:49:32.760 --> 00:49:32.970 Scott: Yeah. 00:49:33.078 --> 00:49:33.408 Will Meurer: you know, a 00:49:33.420 --> 00:49:33.710 Scott: Yep. 00:49:34.058 --> 00:49:34.468 Will Meurer: really. 00:49:34.518 --> 00:49:37.668 And it was-- They, they know it was coming, but, you know, it's 00:49:37.700 --> 00:49:37.930 Scott: Yep. 00:49:37.968 --> 00:49:41.808 Will Meurer: protocol choice we made to say we are gonna do this every 00:49:42.100 --> 00:49:42.270 Scott: Yep. 00:49:43.408 --> 00:49:47.518 Will Meurer: Um, know, we did, we did also design a pediatric trial that has 00:49:47.568 --> 00:49:51.248 many features that are similar to adult ICECAP, but some that are different. 00:49:51.358 --> 00:49:55.728 Um, and one of them is that because there was more equipoise in that 00:49:55.728 --> 00:49:57.388 trial, it does have a no cooling group. 00:49:57.418 --> 00:49:58.938 It has a zero-hour duration. 00:49:59.318 --> 00:50:01.418 Goes all the way out to ninety-six 'cause of that data from 00:50:01.418 --> 00:50:03.908 neonates where seventy-two to ninety-six worked well in them. 00:50:04.288 --> 00:50:06.758 But one thing is we did say that the interim analysis would be 00:50:06.758 --> 00:50:10.208 every, approximately every ten weeks to just make it a little bit 00:50:10.208 --> 00:50:12.458 more predictable, um, and nice. 00:50:12.488 --> 00:50:13.448 But, but, but Dr. 00:50:13.448 --> 00:50:18.758 Yates and the team at MUSC, were phenomenal and, um, we were 00:50:18.758 --> 00:50:20.168 always keeping our eye on that. 00:50:20.778 --> 00:50:24.858 And but, but yeah, but it would, it would change, you know, as an emergency 00:50:24.858 --> 00:50:27.778 physician and somebody who works in the ICU, and I take stroke call, I'm 00:50:27.778 --> 00:50:30.878 like, "Oh, I gotta do something in the middle of the night on a Tuesday." 00:50:30.878 --> 00:50:31.668 I'm used to that. 00:50:32.068 --> 00:50:35.508 Generally, and again, this is not a slight on academic biostatisticians, that's 00:50:35.508 --> 00:50:37.188 not typically part of their workflow. 00:50:37.348 --> 00:50:41.448 Um, but, but they, they, they got everything going so well, and 00:50:41.448 --> 00:50:42.608 it was, it was just a delight. 00:50:43.274 --> 00:50:43.334 Scott: Yeah. 00:50:43.334 --> 00:50:43.374 Yeah. 00:50:43.374 --> 00:50:43.494 Yep. 00:50:43.974 --> 00:50:44.254 Yep. 00:50:44.574 --> 00:50:45.044 Okay. 00:50:45.044 --> 00:50:48.954 We, we need to stop now because we'd start telling results. 00:50:49.334 --> 00:50:55.704 So look for ICE CAP results, uh, coming when we do another interim 00:50:55.704 --> 00:50:57.704 analysis, which we love to do here. 00:50:57.704 --> 00:51:02.444 So thank you, Will, and I look to, to see you very shortly. 00:51:02.754 --> 00:51:07.524 Uh, and thanks everybody, and, uh, thanks for joining us. 00:51:07.574 --> 00:51:10.944 Until next time, we are here in the interim.