Good morning. So the most relevant disclosure is that I'm one of the two PIs for the MIND trial, and so my employer is paid an amount per quarter as part of my salary to run the trial. So this is a multi-center study of Artemis, which is the second generation device that was originally called Apollo, in a randomized controlled trial to look at evacuation removal of ICH. And I'm not going to go into as much detail as Rob did, but essentially ICH is still incredibly common. It's 10 to 15 percent of all strokes, and it's almost something that we've become somewhat nihilistic about. Many of our centers, these patients just kind of rot in the neuro ICU and end up with a lot of troubles related to edema around the hematoma, and they're a real management dilemma at times. I'm sure everyone in the family who's, everyone in the room who's clinically active has dealt with family members trying to decide what the degree of disability is going to be and how aggressive to be. Mortality is more than 70 percent in five years, and most of the follow-ups are dependent on, most of the patients who've had an ICH of significant volume are crippled. The standard of care at this point is really just supportive. If you look into guidelines in the American Heart Association, class one evidence essentially says we've got to control their coagulopathies, we've got to control their blood pressure, and put them in the ICU and try to avoid aspiration pneumonia. We've had multiple surgical trials that have failed, and medical management trials that have shown the importance of blood pressure control. The STICH trials, a total of 1,634 patients showed some favorable outcomes with minimally invasive surgery and a benefit for patients with a superficial hematoma. So this does seem to point to the fact that if we can remove the blood clot and probably do it fairly early without disrupting the brain severely, there's data that seems to indicate there may be a benefit. And then for the Apollo system particularly, we've got several papers out with retrospective analyses that seem to indicate a benefit. This was an early paper where they have the ICH volume without any safety problem, and here's another paper out just two years ago with an average hematoma size over 50 cc's, but a significant improvement in the volume, the midline shift, the mortality, and 30% returning home after hospital or acute rehab, which seems to be a little bit better than what we've seen in other trials. There have also been meta-analyses that suggest that hematoma evacuation will help. So the idea here is to do an RCT and really see if there's a way to be very minimally invasive, get the majority of the blood out, and help patients. So the primary objective of this study is to compare the safety and efficacy of the device with best medical management. So this is a multi-center perspective randomized study with moderate to large volumes who present within 24 hours of symptom onset. So you have to have them enrolled within 24 hours. Yeah, they have to present within 24 hours and you have to have them enrolled fairly quickly as well. And they're going to get follow-up at 7 days, 30 days, 90 days, 180 days, and 365 days. The study will include 500 patients at up to 50 sites. And there are internal analyses built in at about 200 subjects enrolled with an adaptive design that will enable us to end the trial early for futility or overwhelming efficacy. It is a two-to-one randomization. So in enrolling, two-thirds of the patients will receive randomization to minimally invasive clot removal. And there is stratification based on two axes, the hemphill score and whether the hematoma is low bar or deep. The inclusion and exclusion criteria are fairly standard. Patients have to be over 18 years of age and less than 80 years of age. And they have to have a hematoma that measures somewhere between 20 and 80 cc's on a simple measurement methodology. And then there has to be a stability scan of some kind. And this can be an interop scan at the time of your procedure at six hours or greater. This issue of a stability scan I think is pretty interesting. I'm hoping Gustavo will talk about it. But in MISTI they really wanted to make sure the clot had gotten done expanding. And you're seeing an echo of that here. The idea there is this sort of theoretical concern, which is supported by some literature, that hematoma expansion is a natural tamponade. And so therefore if we go in and disrupt a hematoma that hasn't really tamponaded the bleeding, you could have more bleeding. I think there's some data already from ENRICH that seems to indicate that maybe what we want is to remove the hematomas as quickly as possible to avoid the secondary damage that occurs in the perihematoma edema in the living tissue around there. But we still have a stability scan in this study, although it's a fairly short stability scan. The patients have to have a significant neurologic deficit from their hematoma, NIH of greater than six, and a Glasgow Coma Scale between five and 15. Because we're looking at 180 day outcomes, we really want to see functional recovery. There is an analog here to stroke in that I feel like with the early stroke trials, we weren't really removing the thrombus. Some of the earliest mechanical thrombectomy trials, they weren't insuring that there was a block large blood vessel and they weren't insuring they were getting the thrombus out. Some of our early ICH trials, we weren't really careful about making sure the patients were independent at baseline. We weren't really careful about making sure even in MISTI 3 that all of the clot is removed or most of the clot. So we're trying to be very careful and look for patients that we can see a signal where we really improve them. So they have to be independent before this occurs. And the minimally invasive endoscopic surgery has to be initiated within 72 hours of the bleed. And then the blood pressure has to be controlled. That's extremely evidence based. The exclusion criteria I think are fairly common. If you think there's an AVM there, if it's infant tutorial, if there's so much IVH that they've got a trapped ventricle and require treatment for the trapped ventricle. These are things that we think would exclude them because I think they're going to muddy the waters in terms of who we think we can help. Midbrain extension or some reason that you can't do imaging. And then if they have an absolute requirement for long-term anticoagulation, a known hereditary or acquired clotting problem or extremely low platelets. Again, these are going to be disqualifications for randomization. Another issue is you have to be able to get consent from the patient or a legally authorized representative. I think the others are fairly common. You don't want somebody who's got an inability to survive for a year on their own without the ICH. You don't want somebody who's pregnant or has an active sepsis. And we have to have people who will follow up in order to really understand what the benefit is. So this is the schedule of assessments. I apologize that the screen is a little hard to see, but it's fairly common for this kind of clinical trial. And we're looking, as I mentioned earlier, we're looking at their 180-day global disability via a modified Rankin as well as the rate of death at 30 days. The secondary endpoints are all what you would expect. The EQ5D5L at 180 and 365 days, how long they're in the ICU, how long they're in the hospital. One of the things that we see with these studies is you're not having the sort of Lazarus effect that you have with the mechanical thrombectomy. You don't even see recovery on the time scale that we see with treatment of a subdural hemorrhage or a subarachnoid hemorrhage. And so for your center, for your staff, you know, you can't do these procedures and expect the patient's going to pop up out of bed later. This is a very disabling event no matter what. But the preponderance of data does seem to indicate that 180 days we may see a signal. So that's really what we're looking for. And then we've got to do blinded assessments at 180 days with a certified assessor. So you really have to have a team. You have to have a research coordinator. You have to have people who can look at the modified Rankin at NIH. So this is the system. For those of you who have done endoscopic surgery, it's an endoscopic procedure where you use this clot aspirator. The aspirator is fairly simple. It's a wand that fits right down an endoscope. I think I've got an old version of the slides, but it will fit down three different sizes of endoscope. And it's got this bident little agitator that will chew up clot. Unlike a ventriculoscopic procedure, early in the procedure, what you're really doing is operating within a sheath. The clot sort of delivers itself into the sheath and you're just clearing clot, irrigating. And then towards the end of the procedure, often you've got a clot cavity that you can kind of look around in, tampon on bleeding, do what you need to do. But early in the procedure, there's just clot under pressure coming out of the sheath. And rather than using this little chewer, you're just letting the clot come out. And so I just want to talk briefly about our experience in Memphis, which led us to enroll in this study. And sort of how we do the procedures. So there are lots of different ways that you can do these procedures. You can do them in a standard operating room. You can do them in a hybrid operating room. We have a Siemens biplane set up in an operating room and that's what we tend to use. We tend to use the stealth stereotactic system without pins with the axiom system. We don't use ultrasound typically, although colleagues at other centers use ultrasound routinely for these cases. It's a simple burr hole. We find that going down the long axis of the clot is most beneficial. And usually for your typical sort of basal ganglia hypertensive hemorrhage, the burr hole is right on the forehead and that enables you to go right down the long axis of the clot. If for some reason the clot morphology is different, you just want to place your burr hole in such a way that you can get right down the long axis of it. We don't typically chew up clot in the sheath. As I mentioned earlier in the procedure, you're just letting that clot deliver. The aspirator will create vapor and obscure your visibility. And then we use DynaCT, which is a comb beam CT that the angio equipment will do typically at the end of the procedure. Sometimes we'll do a DynaCT look, decide we haven't gotten as much clot out as we'd like, and take another pass. So here's an example of a fairly recent procedure we did. It's two fused DynaCTs. This is before the procedure, on the table what the clot looks like, and this is immediately after the procedure. But having the scans fused enables you to see just how thorough a clot evacuation you can get out. You can see our trajectory is marked there. So we just went just above the frontal sinuses, down the long axis. And it can be frustrating. This is a different kind of surgery than microdissection. Again, different than an erection, that it's endoscopic, you don't get bimanual ability to manipulate tissues. But it can also be very satisfying, and you can get an extremely thorough evacuation of the clot, aiming to leave less than 15 CCs, less than 50% of your clot behind at the end. So this experience that I'm just going to talk about briefly is published and available to you in the literature. But essentially we have a large group of neurosurgeons in Memphis, and some of us are older and have seen failed trials like Stitch. So we wanted to look at our patient population and see if in our early experience with this device there was evidence, even though it's not a trial that proves the efficacy of the procedure, but evidence that we might be helping patients on our retrospective analysis. So what we did was we looked at our consecutive patients with spontaneous ICH from July of 2014 to December of 2017. We looked at all of them who had basal ganglia hemorrhages over 18, and we were able to come up with a cohort of 19 Apollo patients in our early experience and 205 other patients that we managed medically. And then just use propensity score matched analysis to match three of these medically managed patients to every one of our Apollo patients and look at the statistics. So what we found is that in general, the patients that we treated with Apollo had larger ICHs. It kind of makes sense. So our average for our Apollo patients was a 40cc hemorrhage. That was statistically significant. And then they were sicker. So our NIH for the patients that we choose to do minimally invasive cloud evacuation was 21 very sick patients, and the average among the other patients was only 11. Other than those two differences, what you'll see is across a fairly broad range of other indicators, the populations were pretty similar. So the patients we took for minimally invasive cloud evacuation were sicker and had bigger hemorrhages. And then when we looked at the outcome, what we discovered was even though they were sicker and they had bigger hemorrhages, they were much more likely to be alive at discharge. So even with this unpowered analysis, we saw a P value of 0.04, indicating that our discharge mortality in the sicker cohort that underwent minimally invasive cloud evacuation was lower. That does improve functional independence, but it's interesting, and it certainly shows that we're not hurting people more by doing this procedure. Again, this is a retrospective review. When we look at the power calculation, our power to actually detect a difference is only 12%. So I'm certainly not saying, well, this means that everyone has to get minimally invasive cloud evacuation. But when our department looked at this, we really felt like what this meant was this was a viable strategy. A minimally invasive procedure that enables us not to hurt the brain around a hematoma. Evacuate the hematoma. We weren't seeing a lot of rebleeds. Although these are sick patients and we have complications in ICU, comorbidities, while we were seeing a benefit in mortality. So I'm excited, here we are at the AANS. I'm excited to feel that in vascular neurosurgery, we're starting to see more RCTs. We're starting to see surgical trials. And I have a lot of respect for the other trials for minimally invasive ICH, but we're starting to see real RCTs that help us to sort out where we can apply neurosurgical techniques, where we can apply patient selection to improve outcomes for diseases that we know are really devastating for patients. So this is a paper from the Lancet this year that shows that even with sophisticated methods to address various sources of bias, you see a ton of retrospective single center reviews. The absence of randomization precludes protection from confounding and can lead us to erroneously infer that a therapy is beneficial or is harmful. So I think MIND is a well-designed trial that takes the data that we have from MISTI-3, the data we have from STITCH, the data we have from these single center and multi-center retrospective studies, and uses those data in a meaningful way to study up to 500 patients to see if this therapy is beneficial for patients. I am happy to make this presentation available for you guys if anyone wants it. And at this point, we're still enrolling new centers, there are about 15 centers in the next quarter that should be coming online, and we're relatively early compared to NRICH in this trial. One of the things that we're dealing with is just like any other surgical trial, we want to make sure that a center has expertise with the technology and the technique before they start randomizing patients, and so we need to review five cases from a center and make sure that, in general, the procedure's being done safely and that there's relatively little clot being left behind when you do the procedure, because like anything else, technically there are nuances. So, I went to the end too fast, but if anyone has questions, I'm happy to answer them about the MIND trial or about the technique. And if people would rather contact me offline rather than to ask in this environment, I'm happy for you to email me or call me. I think this is a procedure that we're really just in our infancy, and I'm looking forward to seeing where it goes. All right, got some questions. Rocco. What about location, because it seems like, you know, the case you showed, the putaminal hemorrhages do fairly well versus like thalamic hemorrhages. Yeah, I think that's true, right? I mean, that's evident in our clinical experience, and that's evident if you look at the literature. So I think, for outcome, the ideal patient is somebody with a fairly lateral basal ganglia hemorrhage. But I went through the inclusion and exclusion criteria. You know, I had an investigator ask recently, well, what if it's a hemorrhagic transformation of a stroke? And I said, well, you know, if they came in with an ischemic stroke and they had a big bleed, they're probably not gonna meet the inclusion and exclusion criteria. And he said, well, I think a lot of these basal ganglia hemorrhages are, in fact, hemorrhagic transformations of small, you know, Charcot-Bouchard strokes. I said, well, we're never gonna know. So I agree with you that there's probably a gradation there, but as long as they meet the criteria, we're gonna randomize it. So it should come out in the wash. I think there was another question in the back. Yeah, so I've probably done 10 or 12, and I had one patient that had just a giant bleed like 12 hours later, and I was wondering what you do about those. Try not to have them. You know, I think that's obviously gonna be something that we're gonna capture within the trial if it's a randomized patient, and it's just what you would expect. If they need another procedure because they have a big mass lesion and they need another procedure, if the re-bleed is relatively small and you can get them through, then you can get them through. Thankfully, that's a relatively rare event in our experience, although, like anything else, it can happen. I don't know what your experience with that particular patient was. If you have some smoking gun that you know why they had a re-bleed, but a lot of times, blood pressure control can be a difficult thing. I mean, I've seen patients who have coughing, you know, or some other provoking event. Blood pressure goes way high in an early post-operative period, and then you end up with a re-hemorrhage. Was there something that you thought led to that, or it was just out of the blue? Yeah, this post-op scan looked perfect. Had a big re-bleed. I didn't re-operate on him, but he eventually made a, you know, probably a better recovery. What day was the re-bleed on after? It was by the next morning. Yeah, I'm not smart enough to be able to tell you why that happened, or, you know, some algorithm for making sure it doesn't happen, or treating everyone in whom it does happen. It's part of the cost of doing business, in my opinion. One other question. Yes, sir. As far as talking to the family, before we had this procedure, you know, in my younger days, I would say, well, we can do surgery. I don't think it's gonna help when you're kind of putting the burden on the family, whether to let grandma go or not. Later, I would say, you know, I don't think we should do surgery. And I'm just wondering, you know, your method or your technique for talking to families about it. Thank you for that question, because it's something I spend a lot of time on and think about a lot. You know, I think as neurosurgeons, we're used to making clinical judgment on the basis of relatively weak evidentiary support. You know, we get pretty specialized, and we get pretty used to coming in and saying, I think you should have this. I think you should have that, in my experience, X or Y. And in some ways, I think that leads us to be less comfortable talking to a family about enrollment in a clinical trial. Because if you're the expert who knows based on your experience what should be done in every individual case, then how do you defend rolling the dice and doing a two-to-one randomization for a patient with a intracranial hemorrhage? So it has, in my experience, and some of my colleagues' experience, it has created a situation where we have to sort of reset how we talk to families. I think it's, you know, extraordinarily ethical, but it takes a little bit of a different attitude. And so I will typically say to a family, we have early evidence, including a look at our experience here, that seems to indicate there may be a benefit for this minimally invasive procedure that outweighs the risks of the procedure, but we don't really know. And so if that's a procedure you'd be interested in, then what we'd recommend is going into the trial. We do not offer minimally invasive cloud evacuation for an eligible MIND patient outside of the trial. In other words, in the event that I went to talk to a family and they said, well, we like the idea of you doing this procedure, but we don't wanna be randomized, we don't wanna participate in research, what I'd say is, we're really trying to be a responsible group of practitioners here, and we're not just gonna willy-nilly be doing that. So if you're interested in the procedure, got a 67% chance if you randomize that you get the procedure, but that's where we do it. For someone who is not eligible for the trial, you know, let's say, for the sake of argument, you've got a cirrhotic, his clotting factors are terrible, you're not gonna be able to handle their edema in the ICU. We will consider minimally invasive cloud evacuation, we'll consider decompressive hemicraniectomy, but for eligible patients, our neuro-ICU team and our neurosurgical team is fairly committed to that this is how you access the procedure, is through the trial. And I think once we've sort of made that shift, and frankly, my neuro-ICU doctors have been incredibly helpful in this, it's something the team's gotten very comfortable with, talking to families and explaining why participation in this research is worth consideration. Did I answer your question, or did I go off on too big a tangent? No, it does, but maybe for the people who aren't gonna be in the study, so, and you're, you know, trying to decide whether to do the surgery, you're not really convinced it's gonna help, but, you know, the patients, or the families are always having this idea that if you operate, then they're gonna be fine. It's hard to get them convinced otherwise. You know, that's 100% true, too. One of the blessings and curses of our life is that we deal with families that are pretty and ugly, smart and stupid, rich and poor, I mean, all across the spectrum, so it, you do have to try and explain that they've had a stroke. In my patient population, I find that useful. This is a stroke, it's a devastating event. Muscle will re-knit together, skin will heal, bone will heal, brain won't. We're trying to mitigate the damage and help recovery, but recovery is a months and months long process that will likely involve a fight. This is a marathon, not a sprint. I had a quick thought on what you asked about when you're not in the trial. So before, I was part of the studies, and I would have this procedure as a potential offering to a patient, because what we see is that the divergent of the outcomes may not be until six months or longer. I would typically have them sort of understand that we're not gonna do the study, and then three days later, withdraw care and let the patient pass away because they didn't get better from the study, I mean, from the procedure, rather. That I would really only offer it if they're willing to take the commitment of, we'll do everything we can to get her out of the hospital and into rehab instead of the other way around, because that nihilistic approach of, well, if she doesn't get better three days after the surgery, we're just gonna withdraw care. I didn't want to do the surgery on patients and end up in that situation, so I would not offer it if they wanted to go that route, or they thought they wanted to go that route. So here, and then here. What are the FDA indications for the device? This is an on-label use. The device is indicated for the removal of blood or tissue from the central nervous system. Sir? Does the hospital sign influence your decision to quit? Does, but what? What's the spot sign? So spot sign's an exclusion criteria for randomization. But I think Gustavo will talk a little bit about that with Enrich. And what about if the hospital sign disappears? Then that's okay if it stabilizes, right? So you go for surgery or still exclude the patient? So that's the purpose of the six-hour stability scan. So a true arterial spot sign, a true arterial spot sign that is present on your stability scan is an exclusion criteria. If, for instance, they come in immediately after ictus of hemorrhage and their first scan, they had an arterial spot sign, but on their follow-up, it's stabilized, there's no arterial spot sign, then I believe they can be enrolled. Other questions? I appreciate, yes, sir? Did you consider using your exclusion criteria to check the volume of the tumor? Retrospectively, we get that big difference in volume. Do you consider using the one that's more than a quarter of a custom volume? Right, so because we used propensity score-matched analysis, we did end up matching patients that had a higher volume. But the overall analysis showed that we were taking patients with higher volume to the operating room. So we did look at that. It enhances the differences. But it's still a retrospective analysis, right? And we got plenty of those. I'm excited about having a prospective analysis. I think we can have more discussion afterwards. I appreciate the attention and the questions, but I want to turn it over to Gustavo to talk about the EnRICH study.

MIND trial

Artemis device

intracerebral hemorrhages

stroke

minimally invasive clot removal

randomized controlled study