Hello everyone. It's 12:30 P.M. [Non-English content] Welcome both Doctor Per Nordberg and welcome as well Professor and Doctor Jürgen Bardutzky. I will actually not say anymore. I will hand it over to Per to start his presentation about PRINCESS 2 study. Welcome and thank you so much for doing this. Thank you so much. Thanks for the introduction. Now I'm in the presenter view, but I think that will be good for you to see. I'm a clinical doctor. I work as a senior consultant in cardiology and intensive care at the Karolinska University Hospital, and I'm the principal investigator of this PRINCESS 2 trial. I was also the principal investigator of the PRINCESS 1 or the PRINCESS trial that we published some years ago. I will give you a brief overview how we work, who is working and what we're aiming to do. I'm not alone. We are working with a study in eight countries. We have an international steering committee from one representative, at least from one of the countries. We meet on regular basis every other month to discuss the progress. That's how we work, basically. I think this maybe is the most important slide. I would say how both Jürgen and myself is working with RhinoChill and with cooling that you need to be very, very early to basically to be able to do a difference in terms of cooling or to have the most effect. We know that all the animal trials, I would say both in cardiac arrest and other conditions, show that the earlier you start the cooling in an effective way, the more benefit you have of the cooling in terms of neuroprotection. Most of the clinical trials, almost all the studies are performed at a much later stage. They start cooling when the patient arrives at the intensive care unit several hours after hospital arrival, after several other hospital interventions. Basically, they start 3- 4 hours after the cardiac arrest and with ineffective methods. We're studying something, I would say, completely different compared to the other trials. Okay. What do we measure? Well, we measure in most cardiac arrest trials, we don't only measure survival because we know that we can make people survive. What is important is for the patients and the relatives that the patient survives to good neurologic outcome. We use this scale. This is the most common scale, Cerebral Performance Category scale. You see one and two are considered as good outcomes. CPC 1 is complete recovery, neurologic recovery. You can go back to the activities you had before the cardiac arrest. As you know, we're working with a RhinoChill, a very special, I would say, cooling method. It's developed to cool the brain first and then the rest of the body. It's, you put in a nasal catheter, and you deliver a mix of oxygen or air and a liquid coolant. It's very easy to apply. I will show you in the next slide. You can start it wherever you are. If you are at the patient's home, or if you're at the hospital, at the emergency department, or the cath lab or intensive care, it doesn't really matter. It's portable. It's very easy to use. I will show you a very brief movie. Here you have it. It's on the mannequin. You put in the nasal catheter like that. You just turn on the machine where you can decide how much flow from the oxygen or air, together with a liquid coolant. You get this like a nasal spray, but it delivers a little bit longer in the nasal cavity. You cool the patient's brain through conductivity. This is during CPR. You cool the brain first, and then when you have the circulation restored, you will get the cooling of the rest of the body. First, brain. We have showed that in animal trials, and then the rest of the body. This is a completely new approach, I would say, compared to the other studies in cardiac arrest. Okay. I will just give an example, was one of the first patients in the PRINCESS 2 trial. A young guy in the middle of the night had a cardiac arrest, witnessed by his wife, and the ambulance and the advanced life support came after about 20 minutes of CPR. He was randomized to cooling, we started cooling in his home. There was no restored circulation, the patient was brought into the hospital and arrived at the emergency department about 50 minutes later, ongoing cooling. Here we were just about to apply a mechanical cardiac device to restore circulation, he got back his heart rhythm, and so we didn't have to do that. He had a large myocardial infarction, so that was treated and then he came to the intensive care after about two hours after the cardiac arrest or so. He was at a core body temperature of 32.7 degrees Celsius. That's our target temperature. 33 degrees Celsius is our target temperature. He was already at the target temperature at time of arrival of the intensive care. We randomize the patients here during the ischemia, during CPR, compared to what they've done in the other trial. They randomize after intensive care unit's arrival. That's a main difference between the two trials. We are already at the protective temperature when the patients arrive at the ICU. Okay, we have done some studies before. Some of you know that, have followed us. We showed in the former PRINCESS trial that we could, in a selected population, in a selected population of the ones that was included in the PRINCESS 1 trial, we could show a huge difference in CPC 1, you know, that's Cerebral Performance Category 1, complete recovery 90 days after the cardiac arrest. This is more than 12% absolute difference in CPC 1 at 90 days. This is the basis why we needed to continue because we couldn't find a statistically significant difference in the whole group. We saw a difference, but it wasn't enough to change guidelines. This is the basis of PRINCESS 2. Now I couldn't find the hypothesis, but basically it's that if we start very early in this selected population with ventricular fibrillation as the first rhythm, we can improve survival at 90 days with complete recovery. That's the hypothesis of the trial. It's a multicenter RCT. We call the patient as early as possible on the scene. This is just a slide from, you have the map of the participating countries. We have six countries recruiting patients now. This is from our visit in Spain, which we started up. That's the second- largest site, including patients. We were there 1.5 years ago. They have included 80 patients. They have a really good setup for including patients in this trial, with a very good and developed pre-hospital system. Okay. This is the flow chart, very briefly. You have an out-of-hospital cardiac arrest. We randomize patients. We don't know which patient that will go into each group to either pre-hospital cooling or standard care. In the cooling group, they cool or cool at the ICU. In the standard care group, they receive normothermia, which is now in the guidelines. This is a very blurry slide I see now. I don't know why, you can follow the inclusion rate at our website, princess2.org. I think this was maybe yesterday we have 245 patients enrolled. The first year was only Stockholm that enrolled patients. We have added sites, you know, during 2025 and now during 2026. We hopefully we can have full recruitment in September, October. We recruit about four patients a week. We want to go up to five, possibly six per week to be able to finish the study within 2028. Okay. This is just a temperature curve from the pilot phase. We did a publication of the first 100 patients that we have enrolled. You can see that patients after, within one hour from ICU admission, from admission to the hospital's intensive care unit, they are at the target temperature, which is 33 degrees Celsius ±0.5 degrees Celsius. The very good protocol adherence and very effective cooling. We maintain the cooling very well in the intervention group. Then we rewarm them as we want. We're very happy with the results from the pilot trial. Looking forward, we have recruitment in these countries that are here. We are working with some more German sites at the moment. We are working with Oslo. We were there just two weeks ago, and they will start in September. We have five Italian sites. I will go there in two weeks. Hopefully, we get them going also either before summer or in September. That was my last slide. Thank you so much. Thank you so much. Thank you for a very good presentation and a very good overview of what PRINCESS 2 study is all about. With that, I hand over. It's a very welcome to Professor and Dr. Jürgen Bardutzky. To show his project, COTTIS 2. Let's see. Sharing his slides so we can. Thank you very much for the introduction. Can you see my slides, or is it? No, we see. Shall I share? We see you're sharing your screen. Yeah. Yeah. No, not opening. Sorry. Now you can see? Now we can see it, and the floor is yours. Okay. That's great. Thank you very much. My name is Jürgen Bardutzky. I'm here the senior consultant from in Freiburg in Germany from the neurology university, and I wanna show you some slides about the COTTIS trials. I wanna start with a patient we treated three months ago. He was 70 years old, and he had a severe right-sided hemiparesis and a severe aphasia. He was not able to talk, and his NIH was 21. That is a very severe stroke, and we did the image, and you can see here the CTA, and you see here the occlusion of the middle cerebral artery on the left side. We always do this imaging with perfusion, and you can see the yellow is the salvageable tissue. That means that is the tissue that you can save by reperfusion and by hypothermia, and the red one, the small red one, that is dead, tissue of the brain. This patient goes in the cath room, in the angiography room, and you see here the occlusion of the artery, and he got this stent retriever, and here you can see the thrombus we could make outside, and this was a reperfusion. Before we start the angiography and the thrombectomy, we start with the RhinoChill, Per Nordberg described the procedure. We started the cooling before the patient was recanalized, and the patient's temperature, the core temperature, was 34.5 degrees Celsius before recanalization occurred. That means we had cooled the patients during ischemia, and this is the magic point here in this study. We can cool the patient as soon as possible. We can cool intra-ischemic, not as done by all other studies, late after reperfusion. After recanalization, we switch from RhinoChill to the surface cooling for another six hours. That means we have at least 6.5 hours of cooling to 35 degrees Celsius. We used 35 degrees Celsius because we think that this is enough to save the tissue and not to get a lot of disadvantages. We did an image. A day after, you can see here the CT in the middle. The infarct core, what you see here, a little bit dark, is exactly the same as we can see a day before. All the yellow tissue you can see here was saved by reperfusion and was saved by hypothermia. This is an MRI on the right side, and you can see here the core, the white thing, and all the other tissue of the brain was safe. Fortunately, the patient recovered very quickly, had an NIH, a very weak hemiparesis on day three, and he was on discharge at day seven with NIH of 2. That means he had a slight hemiparesis. After three months right now, he had a modified Rankin Scale of 1. That means he can do everything as before, and he's absolutely independent, and that's the goal of the study. Now the explanation why we use hypothermia in a severe ischemic stroke. There are five highly positive studies in the year 2015, these five studies with thrombectomy showed that all studies with thrombectomy had much more patients with a very good outcome compared to patients who did not the thrombectomy. In the mean, about 46% of the patients had this good outcome. Good outcome means a modified Rankin 0-2, that means independency. That's very important. The patient is able to live the life without help from others. In the control group, without thrombectomy, only 26% reached this goal. Now the question, why should we use hypothermia? Because you can't put it in another way. More than half of the patients, despite thrombectomy and despite high recanalization, still remain disabled and need help for living. There's an absolutely need for additional therapies for neuroprotection in addition to thrombectomy. Hypothermia is the best drug or the best therapy in acute stroke and always proved very good neuroprotection, and especially in patients with a large vessel occlusion, hypothermia is very promising. There's first a high recanalization rate by the angiography proven and the reperfusion is achieved in about 90% of the patients. Exactly that is what you need for hypothermia. You need reperfusion. When you have no reperfusion, the brain tissue will die. Hypothermia has no effect on brain tissue that is not reperfused. Another good point is you have a big mismatched tissue. That means you have a small core and a lot of brain tissue that is at risk, but is salvageable, that is still alive. Another point of that hypothermia in these thrombectomy patients is a very promising tool is that the patient is usually under analgosedation, he's intubated. That means he has no pain, no discomfort, no shivering. Most studies in the past use awake patients, they shivered, had pain, and we are not able to perform hypothermia in these patients. The last thing is we start as early as Per already said, during ischemia, because RhinoChill is very fast, very easy to use. We start in the cath lab with hypothermia before recanalization, we proceed with hypothermia during recanalization, and during the critical reperfusion phase for about six hours. In the next slide, I can show you what is the protocol. This is a regular patient without hypothermia. He comes in, we do a thrombolysis or not, it doesn't matter. He comes in in the cath lab, patient got intubated, then the thrombectomy started, the patient will wake up on the ICU three, four, five hours later. In the COTTIS trial, we start cooling with RhinoChill before thrombectomy, directly after intubation. When the thrombectomy is done, we switch to the surface cooling for another six hours, then we warm up the patient about seven hours to 36.5 degrees Celsius. What patient should be included? Actually, all patients with an indication for thrombectomy can be included in the trial. We have two parts of patients. It depends on the time window. When the patient is in a time window within six hours onset, we need a CT and a CT angiography, like you see it here on the right side, and we can include the patient. Then there's the time window, 6- 24 hours. When we want to include the patient for thrombectomy and hypothermia, we need a significant mismatch in the perfusion imaging. This is shown here. The yellow one is the penumbra. That means the salvageable tissue, and the red one is the dead tissue. On the right side now here, you can see a patient. There's a very big area is red, more than 100 ml. This patient cannot be included because we have a threshold of 70 ml of the core volume. What is the primary outcome? The primary outcome is the modified Rankin Scale. There are six points. Zero is no symptoms after three months, one is nearly no symptoms, and two is able to look after own affairs without any assistance. This is termed good outcome. That means the patients with a modified Rankin 0- 2 has a good outcome. This is dichotomized versus poor outcome. That means 3- 6, and that means three is able to walk, but the patient needs help. He requires help in some things in the daily living. Four is moderately severely disabled. He is not able to walk. He needs help the whole day. Five is severe disability. He's bedridden, and six is dead. The end point is good outcome, 0- 2, versus bad outcome or poor outcome, 3- 6. Here you can see the results from the first trial. It was a feasibility trial, COTTIS 1. We could show that within, you see here the temperature curve, within 30 minutes, all patients reached the target temperature of 35 degrees Celsius. The recanalization was about at 60, 75 minutes here. All patients were at the target temperature of 35 or lower degrees. We did this matched pair analysis with the historical groups. We matched it by age and severity and so on. You can see here the temperature of the cooled patients, the blue one. You can see it on the left side also. You can see the red one is the temperature of the control group, and it was always 36 degrees Celsius points somewhat. This was significant at all time points. The outcome that was published this year is that 68% of the cooled patients with 35 degree Celsius had a good outcome, a very high proportion. In contrast, in the control group, almost 30% had a good outcome. That means more than twice of the patients had a good outcome when they were cooled. A very hard trend towards cooling, towards hypothermia in these severe stroke patients. This is the actual randomization part. We have now in March and April three more sites. It's Osnabrück, it's Tübingen, and the other is Essen in Germany. They just starting, and two sites have included the patients last week. We have now six active sites. Seven is wrong here. It's six hospitals recruiting patient right now. We will switch our team in June this year in Freiburg because we need more PIs. We need more senior doctors for inclusion of patients during working times like weekend or the night because this 2/3 of the patients come in not at the regular working hours, and that is the problem why the recruitment rate is not that high as expected at the beginning. The timeline, it is not easy to say, but we with the maybe new sites or the six sites recruiting about 10 patients a month, we will end the recruitment by end of 2027. What is the consequence? What is our goal? We want just to show that by using this fast, easy hypothermia by RhinoChill, absolute 20% of all patients will get a good outcome. That's a big, big number. This will change, of course, the guidelines, the international guidelines to recommend early cooling in all patients with a large vessel occlusion up to 24 hours after symptom onset. This hopefully will be a very, very big step in the treatment of stroke patients. Okay, thanks. This was the last slide. Thank you. Yeah. Thank you so much, and you can stop sharing again. Stop sharing. Yes. Yeah. I try to. Now. Perfect. There we are. Is it good? Okay. Okay. Thank you so much, thank you both of you doing this for us, explaining it in a levels that we all understand, and also making sure that you let us understand what it does for the patients exactly and how it works. I hope everyone has got a good overview. If you have any more, if you have any questions to Per and or to Jürgen, you can still send questions to us through the separate link where we have or collect all the questions, and we will during this afternoon answer most of the question. All the questions that's come in, we will try to answer in the afternoon today. Thank you those who has already sent in questions as well. I'm looking at the time. We have, yeah, two more minutes. I know you are very busy, both of you. I think we have time for questions, so one question each. We have, based on the questions we have got in, for Per then, for PRINCESS 2 study, we have got a question here. I hope you can answer it in a good way, better than I can. Looking ahead, the role of the interim analysis, without discussing data, what scientific or practical insights do you hope the interim analysis may contribute to in terms of understanding the role of the intervention in the acute care pathway? Which of these insights do you hope to share as the study progress? It's a long question. Yeah, a long question, but I can start by explaining how this works. It's normal to have a interim analysis, and that's after about halftime or a little bit before halftime. It's important because it's an independent data and safety monitoring board that reviews our study. We don't see the data ourselves, so we hand the data over to them. Basically, I would say the most important thing is that we look at harm and safety issues if there's nothing coming out from there. Because if they do, if we have that, they might say you have to stop the trial. I, there's no, we don't think so, of course. Then they look at some other, you know, the how do you perform the intervention? Do you perform the intervention as intended? We have of course some stopping rules for both futility and for efficacy, but it's very rarely that you get an advice at this early stage. If you stop a study at 400 patients, it will not be enough for the guidelines because it's too small study. You still- What can come out of it is to have another interim analysis after maybe 700 patients or so. Normally they just say, "Okay, this is good practice. It works well with the inclusion rate, and continue as you do." That's the basic. A normal outcome of an interim analysis, I would say. Thank you. Thank you for explaining. We hope it will come quite soon, the interim analysis. Yeah, we're planning for it in December this year. Yeah. That it goes well. It will exciting time ahead of us. Thank you so much, and thank you for your participation. I have a question here as well for the COTTIS 2. This one, yeah, it's about protocol. Protocol differences compared with CHILL-ART and FOCUS showed positive results when FOCUS was neutral. What do you see as the most important differences between those protocols and the COTTIS protocol? Yes. They just came out at the European Stroke Organisation Conference, the first thing is it is very, very impressive that one of the trial is positive because they just did 30-minute infusion of cold saline, and that's enough to get positive results. The other study, there was a trend and was not, it was neutral, this supports the idea of hypothermia during this critical phase of ischemia and reperfusion. I'm really lucky about that. The main difference is the duration of cooling. We start earlier and intra-ischemic, and we continue to cool the patients for at least six hours after recanalization. They just did it 15 minutes with saline is washed out within seconds, and we have no idea how cold the patient really is in the brain. The duration of cooling is absolutely different to the COTTIS trial. Thank you, thank you for the good explanation. Yeah, I was there listening to these two studies, it was interesting to hear what they had come, how far they had come, also to hear that they will continue to do research on this area as well. We are looking forward to see what they will progress with as well as with our study with the COTTIS 2. Thank you. Once again, thank you both. Thank you so much for doing this for us, keep up the good work with the studies. I know everyone here, it has been over almost 100 persons listening in to you, we are a lot of people that are engaged in your work, we are here with you. Thank you everyone who has joined. As said, if you have any questions, please send them in. With that, we will end this webinar. I think with a big applause to the two stars of these presentations. Thank you so much. Thank you so much. Thank you all. Thank you very much. Have a good day, everyone. Thanks. Bye.