Hello and welcome to today's Journal Club Critical Care Medicine webcast. This webcast, hosted and supported by the Society of Critical Care Medicine, is part of the Journal Club Critical Care Medicine series. This webcast features two articles that appear in the September 2022 issue of Critical Care Medicine. This webcast is being recorded. The recording will be available to registrants on demand within five business days. Log in to myfccm.org and navigate to the My Learning tab to watch the recording. My name is Thomas Zagmany and I'm a Professor of Intensive Care at Cardiff University in the United Kingdom. I will be moderating today's webcast. Thank you for joining us. Just a few housekeeping items before we get started. There will be a Q&A session at the conclusion of both presentations. To submit questions throughout the presentation, type into the question box located on your control panel. If you have a comment to share during the presentations, you may use the question box for that as well. And finally, everyone joining us for today's webcast will receive a follow-up email that will include an evaluation. Please take five minutes to complete it. Your feedback is greatly appreciated. Please note the disclaimer stating that the content to follow is for educational purposes only. And now I would like to introduce today's presenters. Jared Greenberg is an Assistant Professor in the section of Pulmonary and Critical Care Medicine at Rush University Medical Center in Chicago, Illinois. His research interests are in communication and decision-making in the ICU and long-term ICU outcomes for patients and families. At Rush University Medical Center, he is also involved with teaching and mentoring medical students, residents, and fellows. Bonnie Lunsey is an Assistant Professor of Surgery and Vice Chair for Research in the NYU Langone Transplant Institute. She was a member of the surgical faculty at Johns Hopkins before moving NYU Langone Health in 2016. Dr. Lunsey's clinical practice is primarily living and deceased donor kidney transplants, laparoscopic living donor nephrectomies, and deceased donor multi-organ procurements. As the Vice Chair for Research, she is involved in the design and execution of the multidisciplinary and multivisceral clinical trials for all solid transplant patients at NYU Langone Health. Thank you both for joining us today. I will now turn the presentation over to Dr. Jared Greenberg. Thank you, Tomas, for that introduction. Today, I'm presenting our article, Daily Written Care Summaries for Families of Critically Ill Patients, a Randomized Control Trial. I have no disclosures. So investigators have looked for ways that written material might improve the experience of ICU families. So what is known about the benefits of written materials in the intensive care unit? Pamphlets on bereavement and decision-making may relieve some of the emotional burden of families who are making end-of-life decisions for patients. Providing families with leaflets containing general ICU information may improve their medical comprehension. ICU diaries are typically written by family and clinicians during the ICU stay. Reading an ICU diary after the ICU stay may reduce the emotional distress of patients and families. In 2017, Guidelines for Family-Centered Care in the ICU was published in Critical Care Medicine. The author suggested that ICUs provide families with leaflets containing information about the ICU setting to reduce family member anxiety and stress. And they also suggested that ICU diaries be implemented in the ICU to reduce family member anxiety, depression, and post-traumatic stress. The reason these authors had this evidence is because the benefits were seen to be moderate and there were not that many risks associated with providing these types of written communication. So while there's evidence that written material may relieve some of the emotional distress that comes with being a family member in the ICU, none of these studies examined whether written communication could be a form of communication between clinicians and families. So our study question was, can written material be a form of communication between ICU clinicians and families if updated regularly during the ICU stay? In practice, ICU clinicians have difficulty implementing recommended communication approaches for a variety of reasons, including lack of appropriate training and time constraints. Written communication may be particularly beneficial when families are unable to visit the hospital because of personal conflicts or visitation restrictions. And written summaries are commonly given to patients after outpatient visits to improve retention and comprehension of misinformation. So this parallel group randomized control trial was conducted at Rush University Medical Center and Academic Tertiary Care Medical Center in Chicago, Illinois from June 7, 2019 to January 7, 2021. We screened incapacitated patients in the medical and cardiac ICUs who required mechanical ventilation for at least three consecutive days and or were predicted by the patient's physician to have at least a 25% risk of possible mortality. Families were considered for participation unless respective patients met at least one of the following exclusion criteria. The patient had required mechanical ventilation for more than 14 days. The patient was expected to die or transition to comfort measures within 48 hours. The patient was expected to be liberated from mechanical ventilation or discharged from the ICU within 24 hours. The patient was a member of a vulnerable population. The patient's primary physician did not allow participation. We attempted to enroll one adult family member who self-identified as a decision maker for the patient. Family members are excluded if they would not or could not participate in study procedures, need a translation of systems because of poor English fluency, and history of a clinically important cognitive disorder. The participating family member was typically the patient's primary family contact. Participating family members provided informed consent either written format or by telephone. On enrollments before randomization, participants provided demographic information, completed the critical care family needs inventory, a measure of satisfaction with ICU care, completed the hospital anxiety and depression scale, and completed the impacts of events scale revised, which is a measure of stress. In a pilot study, we developed an approach to create written summaries. To standardize the process, we created a template with common problems and management strategies. The initial intended goal of the daily summary was to supplement the experience of ICU family members' participation with the ICU team during rounds, and so the format of the written summary was modeled on a patient presentation during morning rounds. The summaries were organized by problem. They included a short description of the etiology of each problem, described whether the problem was worsening or improving, included any relevant diagnostic studies or therapies. A study investigator used this template to create a summary for each participant, aside to the intervention group each afternoon. Summaries were printed for participants or securely emailed each day, devoid of protected health information. Changes from the previous day were bolded or italicized. Participants were encouraged to discuss any aspect of the summary they did not understand with the medical team. All summaries for the hospitalization could be accessed by the ICU team who were not blind to the group assignments. The primary outcome was the score on the critical care family needs inventory measures during the first week after enrollment or on patient transfer out of the ICU. Inventory outcomes were scores on the HADS and IESR surveys during the first week after enrollment, scores on the critical care family needs inventory HADS and IESR surveys during the second week after enrollment, qualitative analysis of telephone interviews conducted during the ICU stay, and patient outcomes. We determined that 94 subjects per group would be needed to detect a group difference of two points with a two-sided test of alpha, 0.05, and 80% power. We expected that at most 25% of enrollees would not complete the critical care family needs inventory. Therefore, we enrolled 126 subjects per group. Changes in outcomes over time were modeled using longitudinal mixed effect models with random intercepts. Of the 252 participants, 156 were enrolled after March 20th, 2020, a period of restricted hospital visitation through the COVID pandemic. The median number of written summaries received by participants in the intervention group was 10. In this figure, which is published in Critical Care Medicine, there were 888 patients assessed for eligibility. Of these, 531 surrogates were assessed for eligibility, and 252 surrogates were randomized. Participants were mostly female and either children or spouses of patients. The most represented ethnic group among participants was Hispanic. There were significantly more participants in the intervention group who had college or professional degrees than those in the control group. This figure shows the survey scores over time for subjects in the intervention group, which is in black, and in the control group, which is in gray. In Panel A, you can see that at enrollment, the scores on the critical care family needs inventory were similar. This is prior to randomization. At Week 2, but not at Week 1, after enrollment, scores on the critical care family needs inventory were significantly lower among participants in the intervention group versus the control group, indicating greater satisfaction with care. For the HABS and the anxiety sub-score and the HABS depression sub-score, from enrollment to Week 2, the scores improved among participants assigned to the intervention versus the control group. The IESR scores, which is in Panel D, were similar for participants assigned to the intervention group versus the control group. Not seen here are patient outcomes, but respective patient outcomes were similar, regardless of participant group assignment. We conducted a sensitivity analysis because participants assigned to the intervention group were more highly educated than participants assigned to the control group. Inclusion of participant education as a predictor did not affect the interpretation of the original models. We did not find that participant enrollment during a period of restricted visitation due to COVID-19 was not significantly associated with any of the outcomes. There were 56 participants assigned to the intervention group who took part in telephone interviews. Notably, participants did not reveal any negative mental or emotional aspects of the intervention on their experience. In our analysis, we identified five ways that the written summaries increased satisfaction. This was improved understanding of the patient's condition, improved understanding of the patient's treatment plan, improved understanding of patient progress, facilitated communication with the medical team, and provided consistent communication each day. There were also five ways that the written summaries decreased anxiety and stress among families, decreased need to call the I.T. for updates, decreased anxiety from waiting for telephone updates, decreased fear of missing information or not processing it correctly, decreased stress from having to keep one's own written notes, decreased stress when sharing information with families. So our results support the use of personalized written communication to supplement the traditional verbal communication approach as clinicians use to support families of ICU patients. Measures of participant satisfaction, anxiety, and depression among participants assigned to the intervention group compared with participants assigned to the control group improved by the second, but not the first week after enrollment. This suggests that written communication played a particularly important role in the family experience when patients had protracted complex ICU courses. Additionally, participants may have learned to more effectively use and process written information the longer the patient was in the intensive care unit. Participants who received written communication did not view it as a replacement for interactions with the medical team. Our findings suggest that written communication improved participant perception of the clarity and consistency of verbal communication from the medical team. Future studies should examine interventions that combine written and verbal communication since they have unique and complementary benefits. Most study participants experienced some form of restricted visitation. Written communication may have helped participants deal with challenges specific to the COVID-19 pandemic, such as communicating with the medical team by telephone. There's a need for further study of approaches clinicians can take to support families who cannot be present in the intensive care unit. Limitations. The study was conducted at a single center encompassing the first wave of the COVID-19 pandemic. The participants who received the intervention were highly educated, which may have influenced their impressions of written communication. To standardize information in the written summaries and to ensure that the participants received summaries at a consistent time each day, a study investigator created and distributed daily communication. Clinicians may find it challenging to implement this approach in practice, particularly in settings where families do not understand English. The future directions. Further study is needed to evaluate the effect of written communication on the family experience in different settings and different time periods. Learn how to implement this approach in ways that do not burden critical care clinicians. Find situations in which the use of written material is most beneficial. It is possible that in cases where families struggle to feel informed, the time a clinician spends writing communication may reduce the time the clinician has to spend providing medical updates or meeting with families. That concludes my discussion of the article. I have a polling question. What is the main reason you would be hesitant to provide families of ICU patients with written communication each day? A, families may not want to receive written communication. B, families may not understand written communication. C, verbal communication is sufficient. D, it would take too much time. And E, more studies are needed first. So, 50% choose B and 50% chose D. So, B, it has to do with understanding written communication and then it would take too much time. I think I was expecting that most people would say that it would take too much time, and I think that's where research in the field needs to be to determine how the documentation that clinicians already are providing could actually be shared with families in a way that they could understand. I think in some settings, particularly when literacy is low, that families may not understand written communication. I think, though, that this communication is often shared with other family members and that they can interpret the written communication for other family members. Then also in this study, we instructed families to talk to the clinicians about anything they may not understand. Thank you. And with that, I'd like to turn the presentation over to Dr. Lanzi. All right. Thank you, Jared. And thanks to the organizers for inviting me to present this afternoon. I'll be presenting the results of our clinical trial that was published in Critical Care Medicine a little bit earlier in the year. Just a few disclosures here. So I will be reporting on the use of an investigational drug, one without a current FDA-approved indication. This study drug was provided to us without cost by Viteris. The company was manufacturing the drug at the time. They were later acquired by CSL Bearing. No monetary funds were provided by Viteris or CSL Bearing for the conduct of this study. This was an investigator-initiated trial. We did receive some philanthropic funds from a family foundation in New York towards the middle of our trial. And personally, I received research funding from AbbVie and CARE-DX for some investigator-initiated trials that I have authored. And I also run some sponsored clinical trials with Hanson Biopharma and Aloe Vera and Transplantation and have served on medical advisory boards for these three companies. My final disclosure is that I'm a transplant surgeon. I'm not an intensivist, nor a COVID specialist, nor a statistician, nor a pulmonologist. So everything I present should be interpreted in that context. And without further ado, we'll jump into this. So this trial is one that kind of came about at the very onset of the COVID pandemic here in New York. And this is sort of the bird's eye overview. We hypothesized that the IL-6 inhibitor clazekizumab might benefit patients who were hospitalized with severe or critical COVID-19 disease that was also accompanied by hyperinflammation. The study design, this was a multicenter, randomized, double-blinded, placebo-controlled trial started out as a phase two, but transitioned in an adaptive fashion into a phase three trial. And I'll talk a little bit more about how that actually happened. And again, this was not a company-sponsored trial. This was a purely investigator-initiated trial. We enrolled inpatients that had COVID diagnosis and hyperinflammation. The phase two portion of the study, we randomized patients one-to-one-to-one to low-dose, high-dose clazekizumab or placebo in an effort at a dose-finding trial. And then in the phase three portion of the study, randomization was limited to high-dose clazekizumab versus placebo in a one-to-one fashion. And the trial was registered as described. So just to kind of set the scene, I think it's kind of important to understand how and why this trial came about. I have to say it was a little traumatic going back through my phone, trying to dig up some of these photos. I'm sure everyone on this call experienced the gravity of COVID in some way, but having it touched down here in New York when no one really knew what was coming, what we were headed into is still kind of almost unbelievable. And in a matter of weeks, our very vibrant city went from a place where these four guys who happened to be my nephews could live it up in Times Square, visiting from Milwaukee to looking like, feeling very eerily abandoned as I walked into work in the morning. And what was happening in and outside the hospital was even more unimaginable. This is just an image of the refrigerated trailers that ended up lining the perimeter of our hospital at the end of March to deal with the morgue overflow. And, you know, I'm not mentioning this to take anybody back to what was a pretty terrible time, but just to kind of provide the backdrop for how this study came about. The hospital was inundated and we were trying to figure out in the moment how to take care of these patients. And there started to trickle into the literature some information from, primarily from China about what the clinical features of this disease was and how they were, how they were managing these patients. And it started to emerge that some of the most critically ill patients were manifesting what appeared to be a cytokine storm syndrome and that there might be some role actually for immunosuppressing these patients as counterintuitive as that might have sounded. And specifically some case reports started to emerge with the use of the interleukin 6 receptor inhibitor, tocilizumab, in the treatment of some of the patients with the most severe disease. And that was sort of the segue to our involvement in all this as transplant physicians. We had some experience with this drug and obviously we had some experience with immunosuppression. But again, at that time, you know, in the hospital we were in the moment trying to figure out what was the best way to actually take care of these patients. We had oxygen. We had the number of ventilators we had. We had steroids. We had hydroxychloroquine, if people remember that was a treatment at the time that was thought to be of benefit. And then for those who were the most critically ill, there was this option of potentially trialing cytokine inhibitors. And tocilizumab, of course, existed as an FDA approved drug for the treatment of rheumatoid arthritis. And in our hospital, we had somewhere fewer than 10 doses of tocilizumab available, which were all administered to very ill patients within the first week of these COVID patients hitting our hospital. And then tocilizumab was no longer available. And so it was a bit of sort of a scramble to try to figure out what we could possibly do to help improve the care we were providing to these patients who, quite frankly, were dying at a very alarming rate. And so tocilizumab, as I said, became rapidly unavailable, but we in transplant at the time happened to be just about to, prior to the COVID shutdown, implementing a clinical trial of a similar drug called clazokizumab, which is an IL-6 pathway inhibitor like tocilizumab, but unlike tocilizumab, it's a direct IL-6 ligand inhibitor as opposed to a receptor inhibitor. And we were getting ready to implement the clinical trial that later resulted in the publication of this study, where this investigational product was being tested for its ability to treat antibody-mediated rejection in kidney transplantation. And to make a very long story short, a series of brainstorming conversations between us and the contacts we had at the company and our infectious diseases specialists and hospital leadership led to us asking the question of, well, if we could get regulatory approval to give this drug, would we have access to it? And through our contacts and support at the company that was producing the drug, who basically said they were willing to do anything that would potentially help in this very dire situation, offered to if we could obtain regulatory approval to use this drug, they would provide the drug without cost. Again, they weren't going to support a clinical trial or sponsor or fund a clinical trial, but they would give us the drug if we could make everything work from a regulatory standpoint. And so, again, very long story short, that's exactly what happened. And so the steps to designing an investigator-initiated trial in March of 2020 in New York were very simple. Number one, approach the FDA and secure an IND with an approved protocol, which we did. Number two, go to our IRB with a protocol that they were satisfied with and approved, which we did, acquire the drug supply, and then get going. And that's exactly what happened. And this happened over the course of about a 10-day period, which is rather phenomenal in the world of designing and implementing clinical trials. So we initially set out to design primarily a safety study and a dose-finding study, because this was a drug that had never been used in these patients for this indication. And we were hopeful that perhaps we would be able to extract some efficacy information from what we were able to do trial-wise. We initially went to the FDA with a proposal for an open-label, single-arm trial. But they said, absolutely not. If you're going to be using an unapproved investigational drug, you're going to get some data on safety and efficacy, and you're going to do it right. So plan a trial, write a trial, and that's exactly what we did. So we designed this pilot study, and we aimed to include patients that we thought would stand to benefit from this class of drug. So here's the bullet points of the inclusion criteria, which kind of hit the highlights. Adult patients hospitalized, confirmed COVID disease. They had to have significant respiratory manifestations. We used some broad criteria in the respiratory inclusion criteria, the one with the asterisk, increasing oxygen requirements over 24 hours. Yes, a little bit vague, but that was sort of driven by the observation that some of these patients, as I'm sure everyone on the call has seen, could come in on room air or on a couple liters nasal cannula, but there was a phenotype of patients that were going to rapidly deteriorate, and we wanted to be able to capture patients before they fully decompensated and allow them to participate in the trial. And then, of course, we wanted to include patients that had evidence of hyperinflammation because those who didn't would be unlikely to benefit from a cytokine inhibitor. So we had some parameters that we used to determine whether patients were eligible, and these were really based on data that was available. The patients were getting CRPs every day for standard of care. We tried to design a trial that we could do with the information we had, with the resources we had, and with the constraints that were in our face, given everything that was going on and the limitations and resources. We excluded patients who, quite frankly, just seemed unsalvageable and non-survivable. We also excluded patients with potential contraindications to receiving clazokizumab. Our study design initially for the Phase II portion was a one-to-one-to-one randomization between a low dose of clazokizumab, which was 12.5 milligrams, high dose, 25 milligrams, and placebo. And we initiated trial enrollment on April 1st. So when I say it was 10 days from study conception to study initiation, I'm not exaggerating. The setup, as I've said, was very simple. On day one of study participation, we acquired some baseline labs, assessed eligibility criteria, and collected a baseline World Health Organization score. And I'm going to pivot to that just quickly. Most may be familiar with this. This became a popular scoring tool in the COVID clinical trial literature, and it was nice because it was very discreet in its criteria. So it's an ordinal scale, goes from 0 to 10, 0 being an uninfected patient, 10 being a deceased patient, with stepwise increases in clinical disease severity with respect to respiratory function. So this was our scoring scale for capturing clinical status that we used. So again, back to the study procedures on day one, baseline labs, baseline WHO score, randomization, and then administration of the first dose. Again, this was double-blinded. So clearly, as a study team, we didn't know who was getting what nor did those who were administering the dosage. So dose one either placebo or clazekizumab given over a 30-minute IV infusion. On day three, by following daily CRPs, if a patient's CRP level had not decreased by at least 50% when compared to the day one, then patients received a second dose of study drug identical to what was administered on day one. And again this was done in a blinded fashion. On day 14, we captured standard of care inflammatory parameters, specifically CRP and others that were available. We captured the clinical score by the WHO criteria. If patients were fortunate enough to be discharged from the hospital, this visit occurred by phone. Likewise on day 28 and day 60, we captured the clinical score either in person in the hospital or by phone if the patients had been discharged. And end of study was at day 60. There were some additional assessments. We collected the CRP values that had resulted for the patients daily on days one through seven and then rolling assessments of concomitant medications as well as adverse events and serious adverse events. These were done on a day-to-day basis. So again, the phase two design, we started enrolling patients in April and I don't recall the exact time frame, but it was somewhere in the range of less than two weeks. We had initially targeted a 30 patient pilot study with 10 patients randomized per arm and within two weeks the patient, the study was completely enrolled and that was the kind of volume that we were facing at the time. And so we sort of saw both a need and an opportunity to expand this trial to something that was a bit more robust. And so we modified our protocol and we obtained the necessary regulatory approvals from the FDA, from the IRB, to try to turn this into a phase three efficacy study. We brought on board four additional sites to turn this into a multi-center trial and we sort of redesigned our analytical plan and power calculations to inform the study design for a phase three study. So what we ultimately report on in terms of phase three results are our primary outcome, which was 28-day ventilator-free survival. Secondary outcomes included overall patient survival irrespective of ventilator status at 28 and 60 days, the frequency and duration of mechanical ventilation and intubation, frequency and duration of ICU admission, the incidence of acute kidney injury and need for replacement therapy, and then some analysis of the clinical status by way of the WHO scores. And so we defined what we called a poor outcome as anyone with a WHO score of at least six at the various time points. And just to refresh your memory, that is anyone who requires oxygen by way of non-invasive ventilation or high flow, that constituted a poor outcome. And then we defined an improved outcome as someone whose score improved or decreased by at least two points compared to their enrollment score. So these were some additional outcome measures that we evaluated. So this little schematic illustrates how the study evolved and then ultimately our enrollments. So we were randomized 178 patients in total. Of that, in the first phase, in the one-to-one-to-one three-arm study, there were 26 patients who ended up receiving the low dose of clazekizumab. I don't have it broken down into who received the high dose and the placebo in this phase two portion, but moving down towards the bottom of this schematic, ultimately from the phase two and phase three portions combined, 78 patients total received the high dose of clazekizumab and 72 patients received placebo. We were providing daily or weekly data to our unblinded DSMB who is doing analyses for safety and efficacy. And after about a month of enrollment and follow-up data, the DSMB based on interim analyses recommended that we drop the low-dose arm. And so for the phase three portion, that was the rationale for converting to a two-arm trial where patients were randomized one-to-one between high-dose clazekizumab and placebo. And the asterisks here at the bottom are just to remind me that the data that I'm showing just include those from the patients who received high-dose clazekizumab and placebo. We excluded the low-dose recipients from these analyses. In terms of our analytical plan, so we utilized Bayesian models for all outcomes so that we could have some estimates of odds and as well as estimates of uncertainty for binary outcomes that were measured. We used logistic regression models for the ordinal outcomes, the cumulative proportional odds models were used. We adjusted all of the models for some key confounders, specifically patient age, sex, the baseline who score, as well as the clinical site where the patients were enrolled. And we report odds ratios typically as the median of the estimated odds ratios generated by the Bayesian model, and then the probability that the odds ratio is greater than or less than 1, indicating statistical significance, as well as the credible intervals around the odds ratios. So for those who are not statisticians like myself, this is just, I'll just walk through an example of the output from the Bayesian models, as this is how most of the data are presented in this manuscript. So the curve here represents the distribution of the odds ratios for a given outcome that was produced by the Bayesian model. So the median or the 50th percentile in this distribution is what we reported as the most likely odds ratio, so in this case 3.84. That is flanked by these 95% confidence intervals, so the interpretation here is that with 95% certainty, the true odds ratio for this outcome falls between 1.54 and 10.62. The probability that the odds ratio is in excess of 1, so significant, in this case was 99.9%, so high confidence that the true odds ratio exceeds 1, and then the probability that the true odds ratio exceeds 1.25, so a greater magnitude, it was again quite high at 99.4%. So for a favorable outcome, and again this is comparing patients who received classic isomab to placebo, so excuse me, so for a favorable outcome, an odds ratio greater than 1 would indicate benefit to classic isomab. An odds ratio less than 1 would indicate benefit to placebo, and an odds ratio of 1 or 1 that overlaps 1 would indicate no benefit. So the interpretation here is that for this outcome, patients who received classic isomab had 3.5, sorry, 3.84 times the odds of having this outcome as compared to patients who received placebo. And so what was this outcome? This was in fact our primary outcome of 28-day ventilator-free survival. So the interpretation again is that patients who received classic isomab had 3.84 times the odds of being both alive and off the ventilator at 28 days compared to patients who received placebo. And again the confidence here is strong based on these analyses. So looking at some of the other outcomes that we evaluated overall, patient survival, the left panel is overall patient survival at 28 days, the right panel overall survival at 60 days, and this is irrespective of ventilator status. Patients who received classic isomab had 1.75 times the odds of being alive at 28 days and 2.5 times the odds of being alive at 60 days compared to patients who received placebo. And again the probabilities that the true odds ratios were in excess of one were high, 86.5% and 98%. Looking at the clinical status outcomes, this is sort of in tabular format, so as we looked at multiple time points, at least just a little bit easier to kind of go through. So again the poor outcome here being undesirable, if there's a benefit to classic isomab, we would want the odds ratio in this case to be less than one, indicating that patients who receive the drug are less likely to have this unfavorable outcome. And so looking at what we defined as a poor outcome by WHO score of at least six, so requiring non-invasive ventilation or high flow oxygen at these time points, what we observed was that patients who received classic isomab had 0.36 times the odds of having a poor outcome at 14 days, 0.26 times the odds of having a poor outcome at 28 days, and 0.49 times the odds of having a poor outcome at 60 days. None of these confidence intervals overlap one, and the probability that the true odds ratio is in fact less than one is in excess of 98% at all time points. We did do some complementary analyses just to convince ourselves that looking at these data in different ways, our results were consistent with one another. So looking at the improved outcome, which again we defined as having a WHO score that decreased by two points compared to baseline at the various time points, we found that patients who received classic isomab had 2.3 times the odds of having an improved outcome at 14 days, 3.3 times the odds of having an improved outcome at 28 days, and 3.5 times the odds of having an improved outcome at 60 days after enrollment. And again, the probability that the true odds ratio was in excess of one was approaching 100%. And in terms of new intubation, again an undesirable outcome. Patients who received classic isomab had 0.2 times the odds of becoming newly intubated after receiving the medication as opposed to placebo. And then patients who, in terms of ICU transfer, new ICU admission or transfer, those who received classic isomab had 0.26 times the odds of requiring new ICU admission or transfer compared to those who received placebo. And again, the significance testing is noted in these panels. One post hoc analysis that we did that I think is certainly worth mentioning because it speaks to sort of the utility of the drug and sort of treatment guidance, which of course, you know, is important, you know, we wanted to know, was there a subgroup of patients that benefited more than another subgroup from this therapy? And this was really driven by anecdotal observations that the patients who seem to be the most critically ill, so those who had advanced to ARDS-type pictures, very few of them actually sort of climbed out of that hole, and there was a lot of mortality in that group. But again, you know, we were blinded at the time, but that was just the anecdotal observation. And so the question was, is there a point clinically where the disease process is too far advanced, the hyperinflammation has already taken its toll, and cytokine inhibition at that point really is of no benefit. So we tried to define a subgroup based on the diagnosis of ARDS and enrollment. We weren't able to sort of make that diagnosis based on the data that we have because we did not technically meet, we did not have all the data to categorize patients as having or not having ARDS technically by Berlin criteria because we didn't have cardiac testing on a lot of these patients. And so we did kind of what was the second best is we used the hypoxia criteria of a P to F ratio of less than 300 as defining a subgroup, which we called having severe hypoxemia. And so when we did a subgroup analysis looking at those who did and didn't have severe hypoxemia at the time of enrollment, we were able to ask, was this a deciding factor in terms of helping us decide whether there was benefit to this drug or whether there wasn't? So the left panel, these are the patients that did not meet these severe hypoxemia criteria. So there were 123 patients in this subgroup. And these patients appeared to significantly benefit from clazikizumab. So the outcome I'm showing here is the 28-day improved clinical outcome. The patients without severe hypoxemia who received clazikizumab had more than four times the odds of having an improved outcome at 28 days. But if we looked at the patients who did meet criteria that we defined as severe hypoxemia at enrollment, there actually was no benefit whatsoever to receiving clazikizumab. So these patients, again, no benefit. Their disease process was just too far advanced. So the overall findings of our study, I haven't shown all the data, but I showed, I think, what I felt was probably the most important and the most clinically meaningful. We observed that clazikizumab at the higher dose was associated with improved 28-day ventilator-free survival, improved overall survival at 28 and 60 days, lower odds of new intubation as well as shorter duration of intubation. I did not show that data. Lower odds of new ICU admission as well as a shorter stay in the ICU, greater odds of an improved clinical status score at 28 and 60 days, lower odds of overall poor outcome at 28 and 60 days. I also didn't show the safety data, clearly important, but the underlying finding was that we did not observe any differences in rates of adverse events or serious adverse events in the clazikizumab-treated patients compared to the placebo patients. And most importantly, we saw no benefit from this medication in patients who had advanced to, who had progressed to very, very advanced respiratory disease as defined by a P to F ratio of less than 300 at enrollment. This study, of course, has some limitations as all do. The introductory slides were sort of to help you understand why the study evolved as it did over time because by no means does this study read like a typical phase three study. We use a broad, we use broad criteria to define hypoxemia, but again, this was intentional just based on the clinical behavior of these patients and us wanting to really give all the patients at that time an opportunity to enroll in a clinical trial when we had very few treatment options available to us. This study was ultimately conducted over nine months. Our enrollment initially was extremely rapid, but as competing trials emerged, it became harder to accrue patients at that pace. And so having conducted the trial over nine months, as we all know, treatments came, treatments went, hydroxychloroquine was there, then it was not used, remdesivir came onto, into the picture. One thing I should mention is that this study, we did not exclude patients on the basis of any other treatments that they received, unless the treatment was another IL-6 receptor inhibitor. So patients who received tocilizumab or cirillumab were not eligible for participating in this trial, but we did allow patients to receive all other standard of care. And so to that added some variables of sort of clinician-specific treatments, site-specific treatments, all of which we attempted to adjust for by randomization, but clearly, potential limitation of this study. I can't speak to the benefit in patients infected with any of the subsequently identified variants of the coronavirus. Probably most of our enrollment was completed before the delta wave emerged, but at this time, there was no ability to do genotyping of these variants. So we don't know what was circulating in these patients, and we don't know whether it was different or whether there were different strains towards the latter end of the trial. And finally, clazikizumab is a significant limitation in terms of applicability. Clazikizumab remains an investigational product. It's not available for use in COVID-19 patients today, even off-label. And so with that, I will stop and acknowledge this group of people that really sort of poured their heart and soul into this trial at a very interesting time. And I also want to acknowledge the NYU Langone School of Medicine Institutional Review Board, as well as the FDA, the staff. I've had lots of interactions with the IRB and the FDA, and I've never seen people rally the way they did during this time, nights, weekends, phone calls from section directors and IRB directors to make this happen in the time frame that it came about. It was really pretty inspiring and incredible to be a part of. And finally, I'd like to thank the Jack Rudin Family Foundation, a philanthropic organization that did provide some funding to us towards the middle of the trial. Trials cost money. People jumped in on a voluntary basis. We had no money. We had no funding when we started this trial. And so that contribution was able to allow us to provide some staff support, salary support, pharmacy support, to do all the things that one needs to do in a clinical trial that actually costs money. And so I will stop there and leave you with a picture of the beautiful city where I live and work. Thank you for your attention. Thank you very much for both of the presenters for their very interesting talks. And we are at the Q&A section of the webcast, and there are a couple of questions for each of the presenters. I'll just start with Jared. How long did it take for the investigator to write the summaries? And on average, how long this summary was? Can you give us an indication? Yeah, that's a good question. It depended. For some patients, they were enrolled or families were enrolled pretty close to ICU admission, so there weren't a lot of events that had happened beforehand. And particularly during the COVID pandemic, when a lot of the patients were enrolled, patients had very similar medical issues. And so those summaries could be written relatively quickly because there was a lot of repetitive information about testing and plans. I'd say, so on average, the first summary took about 15 to 20 minutes to create, and then subsequent ones maybe closer to 10 minutes. And then how long were the summaries? You know, it depended on how many medical problems were being highlighted, but they probably averaged like one to two pages of typed text. Thank you. Bonnie, our next question is to you. I mean, really impressive results and very impressive work to pull this off in the midst of the pandemic. Based on this data, it seems to me that clozakizumab could be an option in the less severe states. Would you agree with that? Yes. Sorry, was there a follow-up? I didn't mean to cut you off. No, no, no. That was the question. Yes, I think that is probably the interpretation. So more severe than just mild disease, ambulatory illness. But I think the key, and it makes intuitive sense, is to treat the patients at the onset of disease before the downstream effects of the hyper-inflammation have sort of manifested themselves physiologically. So kind of the earlier, the earlier, the better. Thank you. Jared, did the family members use this written summary that they have received in the intervention group as reference guide when they inquired about their loved ones, either in person or on the phone? So we, you know, in the interviews that we did with family members, they did say that often they would receive the summary before maybe the clinical team reached out to them. And so they would have that as a reference that they would either ask terminology or ask questions for. So I think it helped either if the families received the summary before talking to the team or vice versa. If the team talked to the family, then they received the summary. Okay, thank you. Bonnie, if this drug could work again in the earlier state, is the biology pointing towards that it might be synergistic with baricitinib, like tocilizumab seems to be synergistic with baricitinib? Do you have any data on that? I don't have any data on that, but based on the mechanism and the pathway, the JAK2 inhibitors being downstream of IL-6 signaling, you would, one would hypothesize this, but no, it's not something that we, it's not something that we had tested or, and I think at this point, it would, this sort of a trial would be very difficult to do, just given the number of treatments that are available that are preventing severe disease vaccines in these patients. I think it would be pretty difficult to perform a large-scale clinical trial to answer that question. But I think mechanistically, that would make sense to me as well. Thank you. Jared, regarding future directions, do you think that you could, or one could collate the summary or a similar summary from a clinical information system using some artificial intelligence and neuro-linguistic programming tools? Yeah, I think so. I think maybe more like a hybrid model might make more sense where the clinician knows that the family member would be receiving written documents, a written document, and they may organize their progress notes in a way that a computer could decipher what the most important parts are, or if there's terminology that's referenced in the know, like a spontaneous breathing trial that the computer would know to interpret that or to explain to the family what that is, or give like a hyperlink. So I don't think it has to be completely artificial, but there may be a combination of that with the clinician knowing that what they write could be shared with families. Thank you. And our final question goes to Bonnie. Have you done any cost-effectiveness analysis on this presented data? I note that you said that this drug is only an investigational product, but is there any indication for cost-effectiveness? We haven't done that. We wouldn't really have had the data to do that, though I think that there's always cost-effectiveness in preventing intubation, preventing ICU transfer, minimizing time on the ventilator, and minimizing time in the ICU. Those are cost-effective measures. So again, something that you would intuitively think there would be benefit there, but I don't have any data to speak to that directly. Thank you very much. We've got a question from the audience. Perhaps it would be good to use the written material at the family meeting as to answer family questions during the meeting. That's a comment-stroke question to Jared. Yeah, I think the next step of this is involving the clinical team more in the writing and distributing of the documents. And so I agree that at the time of a meeting, the first step could be just going over what had been written so far so everybody's on the same page. But I agree with that comment. Thank you very much. And this concludes our webcast for today. And I would like to thank our presenters and the audience for attending. Again, everyone who joined us for today's webcast will receive a follow-up email that will include an evaluation. And we would be very grateful for your opinion on this webcast. And on a final note, please join us for our next Journal Club Critical Care Medicine webcast on Thursday, October 27th. This concludes our presentation today. Goodbye.

daily written care summaries

family satisfaction

patient's condition

communication

IL-6 inhibitor

clazakizumab

severe COVID-19 patients

ventilator-free survival

clinical status scores

early administration