Transcript Video INTREPID Results & Interpretation < Back to Summit23 Brain Injury Management INTREPID Results & Interpretation Presented by Professor David Greer Thank you very much for having me. I appreciate it and I, I very much wish I could be there with you today. Uh It's my son's my son's favorite football team in Milan. So my apologies. Uh I'm happy to talk with you today about the Intrepid study uh which is a multi years long uh effort uh which uh hopefully will provide some insight to the field. Here's my disclosure slide. Uh And I did receive research support from Becton Dickinson and company to uh be the P I for this study. Um You will know that fever has a significant local effects on the brain, uh which can be detrimental, especially after an acute brain injury. It can increase excitatory amino acids, free radical formation, local acidosis lactate uh production and ischemic depolarizations and it can decrease the integrity of the blood brain barrier, uh decrease enzymatic function and cytoskeleton stability as well. The uh impact on a clinical basis uh was less known until we did a large meta analysis. Back in 2008, we published it where we looked at patients with stroke and other neurological injuries to see what impact fever might have on outcome, uh, and found that fever was associated with worse outcome, regardless of which outcome measure that you use, whether it was the modified rank and scale Canadian stroke, scale intensive care length of stay, hospital stay or mortality across the board. Patients who had a fever after an acute brain injury did worse, uh, uh, in their recoveries. And it really didn't matter based on each individual disease state, whether it was a vascular brain injury or a traumatic brain injury. All all patients did worse uh when fever occurred. Uh However, there haven't been studies to really prove that treating the fever is beneficial. In fact, if you look at the most recent guidelines, this is for the ischemic stroke. They do not uh say that there is a recommendation for using pharmacological or non pharmacological treatments to control fever. If you look at the most recent guidelines, it just out this year for se Acton hemorrhage, they say that fever and targeted temperature management are key questions. Uh and that the questions within including the uh the optimal target temperature, the duration, the modalities to use and the side effects. Uh these are all areas for study but are as yet unproven. And then the 2022 guidelines for intracerebral hemorrhage, very similar uh say that it's an opportunity for future research. Uh But uh at the present time, it's not been demonstrated, control of fever has not been demonstrated to clearly improve improve outcomes and is only a potential therapeutic uh opportunity as is peri hematoma, uh edema, uh whether treating it uh with no theia uh or temper temperature modulation improves outcomes is unclear. So this is why we did the intrepid study is a unmet need in stroke management. It's the number one cause of long term disability in the US uh and likely worldwide as well. Uh And patients who have uh a stroke, uh uh only 10% of patients fully recover. Many are discharged to skilled nursing facilities. It's not just as a disease. Older people, 31% have it below the age of 65. And it could be truly devastating in younger patients as well. And there's a huge cost of it and fever can cause secondary uh brain injury, as I told you earlier and that secondary brain injury due to fever may be uh as bad or worse than the initial injury from the stroke itself. So, Intrepid was a multi center international randomized clinical trial, uh randomized patients to surface cooling to prevent t uh fever with a target temperature of 37 °C versus standard reaction to fever control arm where patient gets a fever, you give some acetaminophen uh or paracetamol, uh and you treat them over and over again and they have recurrent fevers and we thought that might be a good control group. We plan to enroll over 1176 patients with ischemic stroke, intracerebral hemorrhage or seacor hemorrhage. But the study was stopped after an interim analysis uh due to futility for the secondary outcome, which I'll get into the primary outcome was a fever burden, which I'll explain that kind of complicated statistic and the secondary outcome, the primary was modified rank of scale. As the functional outcome, we also looked at other functional recovery scales, mortality, neuropsychological outcomes, IC uh IC U and the hospital length of stay. Uh It was a randomized controlled multi center clinical investigation. Looking at the prevention of fever using the Arctic Sun device, we had 30 us sites, 10 international sites including seven in the eu uh three in South Korea as well. Our first patient came in in March of 2017 and our last patient in 2021 which is when the interim analysis was performed. The primary end point was the daily average fever burden which took into account not just the episodes of fever, but the amount above the uh temperature of 38 was factored in as well. This gave an interesting statistic which has been slightly controversial, but we really wanted to capture not just episodes of fever but the degree of fever uh as well. Uh uh And hopefully we captured that the secondary endpoints are arguably more important than not. The 90 day modified rank and scale score was the primary secondary outcome. And the study was powered for that uh that outcome, we also looked at the uh G OS enih stroke scale bartel index, the mocha score at three and six months, uh mortality, IC U and hospital length of stay and major adverse events in uh including infection and shivering. We included adults nonpregnant patients. This was not a study of Children. You had to have either an ischemic stroke, intracerebral hemorrhage, subac on hemorrhage to get in and you had to be functionally independent prior to the onset, meaning a modified rank and scale of two or better. Or if you were in the 80 to 85 year range, you had to have a modified rank and scale of zero because there were many octogenarians who were being excluded, who were quote good octogenarians going into this, meaning that they had very little disability. So we loosen the parameters to allow those patients to come in. I won't go into all of the eligibility uh criteria here. But again, it was just patients with ischemic stroke and I had to meet to see specific criteria which I'll show you in a minute. But a couple of things that were important for exclusions. First of all, if they had a fever for more than one hour or more than one instance, prior to study enrollment, they were excluded from this style. Th this trial, we really wanted to make sure that they uh we were, we were studying fever prevention, not fever reaction if they had a pre morbid condition that in the opinion of the investigator suggested a poor likelihood of survival to six months. And that was really, again left to the investigator discretion. If they were undergoing therapeutic hypothermia for some reason, then they were excluded from this study or if they were, uh, in the investigator's opinion, likely to require an IC U stay of less than 72 hours. So this is helping to exclude patients with too mild uh injury. We didn't want patients who a weren't going to develop fever and B who were going to do well, really probably regardless of anything that we did in the IC U care. So it was somebody that needs to be in the IC U for at least 72 hours and they had to have a likelihood of survival for at least six months. So hopefully excluding the really bad and the really good on either side here are the disease specific criteria. And again, I won't get into great detail for this. But these are patients who you would expect to be in the IC U for several days. Uh patients could have an ischemic stroke even with hemorrhagic conversion. But the hemorrhagic conversion patients had to fulfill all the IC H criteria as well. Uh in the IC H uh uh uh group, they had to have no less than six hours. And that was because sometimes the hematomas would expand during that time. We figured that, that would at least give them time to have stabilized somewhat. Uh And patients on anticoagulation had to have serial scans. Uh We looked at IC H volume of 1 to 60 CCS, greater than 60 CS, 60 CCS probably indicated AAA poor likelihood of recovery. And they couldn't have an IC H due to neoplasm or trauma, subarach hemorrhage. Again, a stabilization period. After their initial injury, we took any WFNS grade uh and we wanted patients with more blood. So we took modified fissure of 1 to 4 because those are the patients most likely to develop fever. Um We excluded patients who had subarach due to trauma, a nonsecurity aneurysm uh except in the case of somebody with an angio subtone hemorrhage. If they otherwise met criteria, we randomized them again to the, the, the control arm which is uh they would have AAA stepwise standard of care protocol of the uh escalation uh going from paracetamol or Tylenol uh up to uh cooling blankets, ice packs, uh and even a controlled uh device versus the experimental treatment where we use the Arctic Sun immediately upon randomization to clamp their temperature uh at uh 37 uh and patients who receive the Arctic Sun device. If they were not intubate, intubated, they needed a temperature sensing foley for up to 14 days or until discharge from the IC U, whichever came first. Uh If they were intubated, an esophageal probe could be used. Everyone got a second standardized thermometry method, uh which I'll get into what was used uh in this study. But we wanted to make sure we were using a secondary measure, especially in the uh control group who did not typically need a bladder thermo. Uh We did routine shiver monitoring and a step by shiver management protocol was followed if signs of shivering were detected. So, of the 686 patients enrolled, 6, 677 belong to the intention to treat population, which I'll talk about today. We had 433 subjects complete the study and 244 discontinue the study for various reasons. COVID-19 only impacted six discontinuations because remember we started this in 2017. So we were certainly impacted by, by COVID. We were very fortunate that we had a good spread of the different diseases. You can see here that it was roughly a third, a third, a third for ischemic stroke, intracerebral hemorrhage and subactive hemorrhage. This is great because this allows us to do great subgroup analyses within these groups. Uh If it had been very skewed, we might have had less power, but given that we had a good enrollment in the study and good distribution, we have a lot of subgroup analyses to do. Here's our enrollment rate. You can see we were doing really quite well as we entered 2018 and 19 and then COVID hit uh and we, we took it some time to uh to rebound from that, but we eventually got to the interim analysis. Here's just graphically showing the impact of COVID. Uh Once again, uh it took a while to come back. But we did really as a testimony to the, the, the strength and, and dedication of our sites in the study for, for which we're, we're most grateful. As I mentioned, it was a global uh enrollment. We had uh a number of uh of uh centers in the U EU including five in Germany, one in Switzerland and one in Austria. I know Doctor Hell is in the audience. Hello, Raymond. Uh Thank you for all your efforts with the study. Uh great uh global uh collaboration on this. Here's the enrollment in randomization. It may be too small for you to see, but you can see at the bottom, discontinued due to death was 75 patients uh in the fever prevention arm and 73 patients in the standard care arm. No difference to those uh numerically or statistically really. Um And there were other reasons for people to have uh a discontinuation early but death was the the most prominent reason uh in both groups. This is the uh demographics and baseline characteristics. Uh The groups were very uh evenly matched. We had a good number of patients who were less than the age of 70. Uh and it was fairly well distributed between men and women terrific uh racial diversity uh in this trial, this is something I'm very proud of and we could look at differential outcomes based on different races of patients, races and ethnicities. As I said, good distribution between the different subgroups, good distribution between high and low severity as we defined it. In the study. The NIH stroke scale was about 17 for both groups. Uh We had uh a good distribution across the IC H scores, good distribution for the high versus low WFNS scores for the subac and hemorrhaged patients. And the G CS was about 11 on average uh across both groups treatments uh for the study, which would be what you would expect. You had patients with ischemic stroke who underwent TP A uh and uh mechanical thrombectomy. Uh aneurysms were treated by a variety of ways whether it was coiling or clipping. Um More patients received a foley catheter in the fever prevention arm, but still a large number in the uh the standard of care arm uh as well. And here are the secondary methods of measuring temperature. Mm, most patients got a bladder thermo uh proportionately but a lot of patients were using a uh a external uh means of measuring temperature. So here are the results on on fever burden. There was a clear positive uh uh effect of fever prevention. As one would expect we were able to control uh and prevent fever. The overall positive fever burden was 54.7% versus 75.4%. This stayed true across the different um uh disease states. And you can see that several Acton hemorrhaged patients and IC H patients had more fever uh across the board. Uh And that's what would be expected. Uh We knew that more blood in the head typically uh correlated with a higher risk for fever. And that's exactly what we saw in a non parametric analysis based on the intention to treat. Uh we can see that for each disease category. Again, the daily average fever burden, that statistic that I showed you earlier was less in the fever prevention arm. Uh This is fever prevention versus standard of care in ischemic stroke, intracerebral hemorrhage versus uh I'm sorry, intracerebral hemorrhage of fever prevention versus standard care and then subactive hemorrhage. You can see it an even more robust uh decrement in the the fever burden for the fever prevention group. This is across the 14 days of this study. And you can see that early on there looks like there's a nice separation between the groups in terms of the temperatures. And then later on what happens is the the end just simply starts to drop off plus patients came off of therapy, especially for those who couldn't tolerate it. And so the lines start to cross. So I think it's a little better to look at the first five days of therapy. And this is what's shown graphically here that we really were able to separate out uh the patients and keep the temperature lower in the fever prevention arm. So if there's a question as to whether we achieved our primary uh objective, which was to uh control fever. We did that. Uh was it perfect? Absolutely not. But we did statistically uh benefit patients by at least controlling their fever. Uh Some people like a statistic of total hours that people wear febrile And I'll point this out to you here. Uh Here's the mean and the median, this is fever prevention versus standard of care. And the total number of hours that patients were febrile were obviously lower uh in the patient who were in the fever prevention arm. Uh It, it was less of a difference in ischemic stroke, look at the difference uh in the subac hemorrhage patients, for example, uh about AAA 20 hour difference in the total number of fever episodes by hour in the binary analysis analysis on the MRS scores. And this is the important part of the clinical outcomes. You can see that there was statistically no difference uh in the uh the MRS scores uh in the intention to treat population. And that did not matter based on what the disease category was. It did not matter whether it was measured at three months, six months or 12 months. We did not find a difference in functional outcome. Here's a modified rank and shift analysis uh where there was again, no, no significant difference between uh the groups for uh showing a benefit based on the modified rank and scale score. Uh This is based on the intention to treat for the Barthel index score. And again, no statistical difference. None of these had a positive uh p value. Uh And uh and it did not matter at three months or six months or by disease category. Same thing for the G OS E uh no significant difference uh based on uh the fever prevention, uh arm versus standard of care. And the moa score is looking at some crude neuropsychological outcomes. No differences in this. Although I'm very happy that we did include some neuropsychologic psychological outcomes in this study. And more studies need to do this in the future to see what the impact might be on more subtle uh areas of recovery. So I think at least it's in inclusion itself was a good thing. The number of days of delirium, there was a concern that by using this device and using drugs to control shivering while people were on the device might impact uh delirium. Uh And we found that there was no statistical difference between the groups in terms of delirium in the acute phase, which is the four first 14 days. And so that was reassuring uh in terms of hospitalization duration, no significant difference. It was not, it did not result in a longer length of stay if you receive fever prevention uh with the device versus standard of care and the IC U duration itself, uh in number of hours was not significantly different uh in the uh fever prevention arm as well. So if there's a concern that by using uh this uh this method or approach that you might increase length of stay or IC U DU duration, uh that was not uh uh uh found to be true in this study. And, and similarly, with the number of days on a ventilator, there was no significant difference whether you got fever prevention or not. And we thought that that could be a problem that if patients were receiving more sedation, it would take longer to wake them up, uh and get them extubated. Uh But we did not find that in the, in this study, thankfully, in terms of major adverse events and these were ce c adjudicated. Uh There was no significant difference, we looked at specific things such as um uh pneumonia, sepsis and cerebral edema as well as death. And although uh some of these might be numerically higher in one group versus the other, there was no statistical difference uh between the groups which was good. Uh And when we looked at it through uh six months and 12 months, that effect was durable. There was no uh statistical difference in major adverse events, shivering, however, was significantly different. As you can imagine. Uh patients who are using the Arctic Sun Device, even for a controlled no theia, like in this study, you can still shiver, uh, because the pads can get cold as you're trying to mount a fever, the pads will get colder and that will potentially induce shivering. So, shivering was certainly something that we, uh, saw a lot of, in this trial, we got very good at treating it. Um, and some sites took longer than others, uh, to, uh, be able to treat it. But one of the biggest lessons learned is to jump on the shivering as soon as it starts to occur to occur. You don't want it to get to uh a higher B SAS score uh and more severe shivering because that's much more hard to, to control it may be detrimental to the patient. Uh And so jumping on early shivering was really key and even preventing shivering before it started. So that is a study I have to give thanks to my uh steering committee and my co P I Kevin Scheff, who I I couldn't have done this study without him and without them, we had Neri Bejaia from University of Maryland, Mary Mary Gusi from Mass General Raymond from uh from Innsbruck, uh and Song co uh from Seoul National in Korea. Uh And what a, what a terrific group. And I'm so thankful for uh all their hard work on this study. So, in conclusion, in Intrepid demonstrated that fever prevention in the acute setting after vascular brain injury is feasible and safe. Uh a beneficial effect on outcome remains to be demonstrated. Important considerations for future studies include patient selection, duration of therapy, uh and shiver management. So I hope I've given you something to think about. Uh And I will stop the talk there and be happy to take any questions that you might have. Thank you so much. Thanks David for having shared with us the detail of intrepid. Uh Congratulations again for this great work. Uh Do we have a question from the audience? Please use the mic if you want. Uh I can start maybe with the first one you, you mentioned already some of the lessons learned because it's difficult now to jump up the results. Uh but uh it will be probably published soon which are the, the, the the big lessons you have learned, for example, for future trials, how Intrepid will inform you for create a new trial on temperature management setting? Well, I think one thing that we learned was making sure that sites were really uh well educated about how to handle shivering. I think the shivering was the the big one and I was a bit surprised to be honest with you because I thought we're keeping people nor the what's the big deal? Uh It should be easy to keep them from shivering because they're just going to be at normal temperature. However, we, we found that that wasn't the case and we likely early on had a lot more shivering than we would have liked and could that have contributed to outcomes? I don't know. Uh but I think that that would have been number one, number two is in awake non intubated patients. This is a very difficult trial to do patients became uncomfortable and you really needed to provide them with a lot of reassurance and comfort and then they still discontinued prematurely in some cases. So maybe selecting more intubated patients and only cooling them during the intubated period may be wise and perhaps selecting within the subgroups of patients who have ischemic. I'm sorry, who have intra hemorrhage and subone hemorrhage primarily uh may may be wiser because they develop more fever. So in patients who never develop a fever, which is about 30% of our population, there's probably no benefit whatsoever to having a fever prevention device. So selecting patients who are most likely to get a fever, I think that would be a really key uh way to design a future trial as well. Um If there are no questions, I have a second question for you. Um you have shown of course that you can separate groups in terms of temperature control, a burden of fever. But of course, clinically speaking, uh I wonder whether the next step would be that if you demonstrated that the less aggressive control of temperature provide the same results than the prevention of fever? Do you think that the future will be a have a control group, whether there would be a permissive hypothermia to be compared with aggressive and preventive fever, that would of course much, much more separate groups in terms of temperature that would create a larger gap in terms of management. And maybe we can respond to the question of whether, you know, controlling temperature versus permissive hypothermia might be maybe the next step to be evaluated. That's a terrific question, Fabio. Uh The, um I know that the TT M three study is looking at, uh just that issue in cardiac arrest patients. Uh And I'd love for us to do that in uh in vascular brain injury patients as well in the US. At least, I think you'd have a hard time talking people into not treating fever. I don't know how it is in Europe, but I think our, our hospitals would think that we're nuts. Uh So I think that would be a hard sell, but maybe if TT M three shows us that there's really no benefit to treating fever at all, then maybe we could translate that over to vascular brain injury patients as well. Created by
