Good morning and welcome to everybody. My name is Ishak Latt. I will be moderating this session on international critical care trials groups, where critical care research is headed in the future. This will be a very interesting panel, where we have critical care research trials group leaders from different parts of the world coming up and providing brief updates regarding the multi-center trials that are going on within their group. So with that, we'll go ahead and lead this off. Our first presenter will be Dr. Flavia Mercado, where she is one of the leaders of the Brazilian Research in Intensive Care Trials Network. Welcome, Dr. Mercado. Thank you very much. I'm here representing BRICNET, which is the Brazilian Research in Intensive Care Network. We were launched on 2009, relaunched on 2014 with the aim of doing high quality research. Since then, we've been doing good meetings, having fun, and publishing high quality research. These are three of our most important publications in the last few years. You might have seen them. The checklist ICU, the ART trial, and the ICU visits. The three of them published in JAMA. The three of them were preceded by their respective study protocol publication in their SAP. We believe that we are a young network, but growing fast. We are preparing our teams. We believe that it's important to build research capacity. This is one thing that we are launching recently. This is going to be our first clinical research. It is in Portuguese, I see, I know. It's going to be our first clinical research course. It's on March this year. We're going to be 100 people, and it's sold out. We are very happy. We have a waiting list for this. This is how people are leading with BRICNET and with research in Brazil at this moment. They are willing to participate in clinical research. They are willing to participate in our trials. And we are willing to participate with other research networks as well. For instance, this is us in HALO study together with the Canadians and other research networks around the world. And we also joined the Remap GAP. But this presentation is about studies that we believe are coming from BRICNET, and we will change practices in the next five years. And certainly, BASICS will contribute to that. As you might know, this is a RCT run by Alexandre Cavalcanti and Fernando Zampieri. They are the PIs. It's run by HCOR together with BRICNET with grants coming from our government. This is a factorial RCT aiming to answer two questions. The first one, it's comparing plasmolyte with normal saline. And the second one is if it's better to give a fluid infusion in 30 minutes, 500 ml, or in one hour and a half. We are randomizing 11,000 patients, and it's a double, a real double blind study. We don't have solution A and B. We have A, B, C, D, and F. Three of them are plasmolyte. Three of them are saline. And I have, my team has randomized more than 600 patients to this trial. And I have not a single clue what is saline or what is plasmolyte. So it's really double blind. Where we are now, up to finish. But let's see. Our primary outcome, we're going to be mortality in 90 days. We have a lot of secondary outcomes, more focus on renal failure and, of course, mechanical ventilation free days and other organ dysfunctions. We have 76 active sites that has already randomized 10,800 patients in less than three years. We started on, more or less, on June 2017. We are randomizing now up to 100 patients per month. And this is our picture. So actually, I believe that if you could randomize better in the weekends and during the night, we would do it even faster. So what we are going to do now, we are going for 11,500 because this is a deferred consent trial. So, of course, we are going to miss some patients that are going to withdraw consent. We might lose some patients because of follow-up. Our rate now, it's about 2% or 3%. So we will include more 500 patients maybe. So we are scheduled to finish the trial on March. And this is our scenario now. We are almost 100% of the included patients have completed CRF. It's less than 5% of uncompleted data. So we believe that after finishing the inclusion period on March, we will have the follow-up until June, cleaning data until August, and preparing to launch it on critical care reviews on January next year. Why we believe this will change practices. If it's a neutral trial, we will contribute to show that we can use a line. If it's not neutral, we will see. And the second part of the trial is also very interesting. The second question, would we really need to give rapid infusion when we try to resuscitate a patient? So there is a second question. Everybody that talks about basics are always talking about plasmalite versus saline. But there is a second very interesting question behind this. But we will have to wait until CCR 2020. The second trial that we believe will change practices is donors. Donors is a cluster randomized trial to evaluate the implementation of a checklist in potential brain-dead donors. It is run by Glauco Westphal, who is presenting also in this meeting. It's run in Moinhos de Vento, another one, another of these excellence hospitals that can have partnerships with our government. So it's financed by the Brazilian Minister of Health. We are randomizing ICUs to the interventional group, which is the application of a checklist to optimize the care of this potential organ donors. The control group is just usual care. There is a co-intervention, which is optimizing communication with the family members. This is the checklist. Of course, it is in Portuguese. The primary outcome is loss of potential donors due to the cardiac arrest. And there is also very interesting secondary outcomes. We had this trial in almost all Brazilian states. The study protocol is published. The SAP is submitted. We had 63 ICUs that included 1,500 patients. We already finished inclusion. We are locking the database this month. It's cleaned. As you can see here, we had the careful, we had the intention that each cluster enrolled a maximum of 30 patients to get a better balance. All this, the selection process of these sites were the top sites in Brazil in organ donation. So they have a lot of patients that are potential organ donors. So we are talking about 60 very busy hospitals in terms of organ donors or potential organ donors. And why we believe that this trial might change care. First, because we can have a P value less than 0.05, showing that this implementation process, this quality improvement initiative, can really change our primary or secondary outcomes. Okay, these are going to be very good. But I can have, I can give personal testimonial here. I was one of this interventional ICUs. And of course, after finishing the trial, also the control arm received the adequate training in the quality improvement initiative. And I can assure you that we are not taking care of our organ donors as in the same way we did before donors. So I believe we already changed practices in the 60 ICUs, even if the P value is not less than 0.05. And a new study, our first attempt in an adaptive design. This is going to be very challenging for BRIC-Net. What we are doing, we are randomizing patients with respiratory failure to a high-flow nasal oxygen therapy and comparing it to a non-invasive ventilation. It's an adaptive design, non-inferiority trial. The PIs are Israel Meyer and Leticia Dorado. Again, it's age core. Again, it's a grant from our Minister of Health. We want it to be, this design has a non-inferiority, but with a possibility to go for a superiority in reducing the proportion of patients who require endotracheal intubation. So our primary outcome is going to be intubation rate within seven days. There are lots of secondary and tertiary outcomes. And inclusion criteria are going to be adult patients who are admitted in the ICU or in the emergency department and who are going to be transferred to the ICU later on with hypoxemic acute respiratory failure, both in non-immunosuppressive patients. There is a second group in immunosuppressive patients. There is a third group who is hypercapnicus, COPD, and a fourth group, patients with acute cardiogenic pulmonary dementia. We're also going to work with deferred consent. It was quite hard to convince the National Ethics Committee to give us the right to do this trial with deferred consent. It's going to be impossible to do it without deferred consent, but we will do it with deferred consent finally. And the patients are going to be randomized and followed until 90 days because of our secondary outcomes. We have never done a adaptive design before, so the people from HCOR had a partnership with Berry Consultants to develop the statistical analysis plan and the adaptive design for this trial. What is going to happen? I'm not on the steering committee of this trial. I am. I was in the other, all the other trials. But they were going to randomize a maximum of 2,000 patients. There's a plan to have six interim analysis. The first one we're going to be with 500 patients. And the second interim analysis is planned after 250 patients. And of course, they're going to change based on the adaptive design. If the group is not stopped, you're going to be an interim analysis each, every each 250 patients or less patients, depending if the group is stopped or not. Where we are now? Well, we are a little bit behind of our plan because we have 11 active sites. And we're supposed to go for 30 active sites up to the end of the year. These 11 sites just started on November last year to recruit patients, a little bit slow. But now we speed up and we are recruiting about eight to 10 patients per week. So we believe that when all the 30 sites we're recruiting patients, we will be able to recruit three times more, which means 30 patients per week. So which means that we believe that at the end of the year, we are going to have the first interim analysis with the 500 patients. We believe this will change practices because we're going to be one of the biggest or maybe the biggest trial with high flow oxygen therapy in four different groups of patients. So let's see. If you can speed up, maybe in one year more on the end of 2021 or on the half, on the middle of 2022, we might be, have finished this. And what more? This is not an RCT, but we believe that this might not change our practices, but change our way of thinking about sepsis attributable mortality. This is impact to MAPA. The PI is Fernando Zampieri. I am on the steering committee of this trial. It's a joint initiative between, again, H-Corps, our Minister of Health, Bricknet, and Instituto Latinoamericano de Sepsis. What we're trying to do, it's a case control study. We actually have 34 sites. The vast majority of them are public hospitals in Brazil. And we are looking at the last 50 deaths of each of these hospitals and the last paired 50 patients who survived. We already have almost 3,000 patients in the database. We did not adjudicate the diagnosis of sepsis yet. We only have it like it was in the database. We are going to adjudicate this. But at a first glance, it seems that at least 50% of those patients who died in the hospital had sepsis in their clinical charts, which, of course, I'm not saying that the attributable mortality were going to be high, but I believe it were going to certainly be much higher than what we believe it is the attributable mortality for sepsis in high-income countries. So we're going to have a good picture of what is the attributable mortality for sepsis in the middle-income countries, but even more important, in public hospitals in the middle-income country. And last but not least, something that Bricknet will produce in the upcoming years. It's the impactful MR. Impactful MR is a platform of 50 ICUs. It's already running the first phase. The first phase is just observational data. We are collecting data on antimicrobial resistance, the economical impact of MR, and the prevalence of MR colonization, infection, and the risk factors for this. After this first phase, which is going to take one year more, we are planning interventional studies in the same platform. And I believe that these interventional studies that will be conducted on this platform of 50 ICUs will certainly change our practices in the next five or maybe ten years. So this is the message that I bring from Bricknet. This is the Bricknet Scientific Committee, brilliant minds that are conducting research in Brazil. And I thank them very much. Thank you all. Thank you, Dr. Mercado. We will actually hold questions until the very end. Dr. Mercado has a conflicting schedule, and so at the very end we hope to provide a round table of all the different speakers and their updates. Our next speaker is from the ANZICS group. We have Dr. Rachel Park, who is coming here to give a brief update regarding ongoing trials from Australia. Thanks for the invite to talk today, and just to update you in terms of where the ANZACS clinical trials group is. So what we'll do today is just have a look about where we've come from, some of our currently recruiting studies, and some of our four newer trials that are employing some novel trial designs that might be of interest to people. Now, we know that the most impactful research in critical care comes from trials groups that are led by investigators who are clinicians that are asking questions arising from day-to-day care, and that's really important to us. And what trials groups do is. There. Trials groups undertake mainly comparative effectiveness research, evaluating treatments which are in widespread use, but for which it is not known which is best. And our research agenda really reflects the questions that practicing clinicians ask. So currently, there's around 36 national and regional research groups conducting investigator-led clinical research in the area of critical care and care of the critically ill. So this includes the ANZACS Clinical Trials Group, which currently has around 78 member units in Australia and New Zealand. We're well-supported by three method centers, also. And we've just got our first international member as well from Taiwan, which is fantastic. So the ANZACS Clinical Trials Group was formalized in about 1994. And we've grown. We started out very small. Our early studies really built the network, built our track record, and built infrastructure. And that's really important. Largely unfunded studies. Now, we've grown. We've randomized over 64,000 patients into clinical trials alone, received large grants, wonderful amounts of funding to keep us going, and published in multiple journals. And we have a network of around 700 clinicians and researchers, research coordinators, involved in 41 active studies at the moment. So some of our currently active studies that you may have either heard of or will certainly hear of once they're completed, I'll show over the next couple of slides. So BLING-3 is a phase 3 randomized controlled trial investigating continuous versus intermittent use of dosing of beta-lactam antibiotics. LUCID is a study comparing liberal glucose control to standard care in patients with pre-existing diabetes. NITRIC is a great study. It's a large randomized controlled trial investigating the use of nitric oxide during cardiopulmonary bypass in pediatric patients with congenital heart disease. And PATCH is investigating the use of pre-hospital tranexamic acid in trauma patients. There's also the large PLUS study. So like the Brazilians, we're fascinated with fluid use. And PLUS will enroll about 9,000 patients randomized to either plasmolyte or saline. The REMAP-CAP study I'm about to talk about shortly. TAIM is a study investigating the use of mild hypercapnia in resuscitated cardiac arrest survivors. And TEAM, it doesn't pay to have two trials with very similar names, trust me. TEAM is a trial looking at early activity and mobilization in the critically ill and ventilated patients. So quite a lot happening. Now, these trials are ones that are just sort of in the setup phase and include BONANZA, which is a trial comparing brain tissue oxygen optimization using ICP monitoring. CLIP2, which is comparing cryopreserved platelets to liquid stored platelets for bleeding and cardiac surgery patients. EPO-TRAUMA, comparing EPO to placebo in trauma patients. And HELP-ECMO, which is investigating different strategies for anticoagulation on VV-ECMO. So quite a broad range of areas that people are investigating still. For a long time, the multi-center randomized controlled double-blind trial has been considered the gold standard of clinical research and critical care. And really, the main study design used by the ANZACS clinical trials group and other trials groups to answer questions regarding care of the critically ill. However, randomized controlled trials are not always feasible or ethically possible. And we also don't want to be putting all our eggs in one basket. We want to be looking at different designs, different ways of understanding what we do. So we've been left to consider as investigators whether there are alternate ways of generating evidence to answer comparative effectiveness questions and improve and guide patient care. So what I'm going to do now is just give you four examples of trials that are currently endorsed by the ANZACS clinical trials group and either have commenced or are about to commence that involve slightly different study designs and ways of doing research. So REMAP-CAP is a global trial designed to improve the evidence base for the management of patients with severe community-acquired pneumonia. Now, traditional randomized controlled trials evaluate modalities or strategies of treatment sequentially, which really can be a lifetime of work. And most of us don't have long enough now to do this. So REMAP-CAP uses a platform trial design known as a REMAP, a randomized embedded multifactorial adaptive platform. And this allows us to simultaneously evaluate multiple treatment strategies for CAP, as well as to evaluate the interactions between the interventions, to determine whether interventions may have differential effects based on characteristics of the patient, and to use the accumulating evidence during the life of the trial to guide randomization to interventions that are actually more likely to benefit the patient. So a REMAP trial has a number of important features. It's randomized, minimizing bias, and generating high-quality evidence. It's designed to be embedded into clinical practice. And this is hugely important so that clinical staff are able to randomize and deliver the interventions as part of the usual processes. And this includes managing the complexity of the design with an online randomization system and using open-label interventions, which I'll show in a minute. We're able to evaluate multiple aspects of treatment simultaneously and investigate the interactions between them. Frequent Bayesian adaptive analyses guide adaptive randomization and pre-specified statistical triggers to determine superiority, inferiority, or equivalence of the interventions that are being tested. Now, in addition, domains can be added or removed over the course of the trial in response to important clinical questions. And finally, the platform provides a means for studying the best way of treating community-acquired pneumonia. And what we've done is paired this with a registry, which will link all patients admitted to the ICUs with community-acquired pneumonia to existing health care databases in each region. So there's currently four active domains within the REMAP platform. The first is an empiric antibiotic domain, which compares four antibiotics, three of which are beta-lactams given in combination with macrolides. And these are given at the discretion of the treating clinician and can be changed as microbiological results become available. So the macrolide duration domain is nested within the empiric antibiotic domain and evaluates the standard course of macrolides with macrolides discontinued at three to five days versus an extended course of macrolide therapy discontinued after 14 days or hospital discharge, whichever happens first. Steroids, the steroid question doesn't go away. So we've also got a corticosteroid domain evaluating three strategies for the use of systemic corticosteroids, the options being to either withhold systemic corticosteroids completely, a fixed duration of seven days, or hydrocortisone while the patient is deemed to be in septic shock. There is also an influenza antiviral domain. So patients with suspected or confirmed influenza might be eligible for this domain. The interventions are, again, to either withhold antivirals completely that are active against influenza or to deliver a five-day course or a 10-day course of oseltamivir. Now, in addition to the domains that are currently available, we're developing a domain evaluating mechanical ventilation strategies and a couple of domains around oxygenation and hemodynamic management as well. So a really important aspect of RemapCap is the platform it provides for responding to respiratory pandemics, which manifest as severe community-acquired pneumonia admitted to ICU. The existing platform of RemapCap is able to adapt in a number of ways in the event of a respiratory pandemic. And these are outlined in a pandemic appendix to our core protocol. And these are pre-approved. So adaptations may include the introduction of new domains that are specific to the pandemic infection, the use of a separate model to analyze patients with suspected or confirmed pandemic infection, or changes to endpoints or inclusion criteria. So we did already have this underway. But in response to the novel coronavirus, we're developing a new domain that we hope will be ready in four to eight weeks. And this domain will investigate Kaletra and interferon 1B both individually and in combination. In addition, the existing corticosteroid and macrolide duration domains may have a role in immunomodulation in the novel coronavirus. What we have done, though, is adapt our primary endpoint for the event of a pandemic, which will be days alive and outside of ICU at day 21 following randomization. So currently, RemapCap has enrolled around 400 patients in 53 sites in 13 countries and more coming on board all the time. So a great global achievement. Now, registry-based trials offer great promise. So there may be some questions regarding data quality and external validity that perhaps remain unanswered. We're lucky down our end of the world. We've got the ANZAC's adult patient database, which contains detailed clinical and outcome data from over 2 million patient episodes now from around 90% of the intensive care units across Australia and New Zealand. And what we're moving to try and do is use this data within our trials. I'll give you some examples. So we know that ECMO use has increased rapidly. It's doubled in Australia and New Zealand in the last five years and apparently quadrupled in the USA. And the Excel partnership represents a novel coordinated effort to try and create a high-quality detailed prospective registry of patients requiring ECMO. Because despite increasing use and high costs, we're still left with significant evidence gaps. Patient selection is unclear. Services vary across regions. For instance, now neck of the woods, retrieval is very common. So there's a lot of areas for future research. So a tailored, detailed ECMO registry, which we've called Excel, can be used to address specific safety concerns, clinical questions, and process of care issues. So the outcome for the registry is disability survival at six months, which is measured using the HUDAS score. This is a prospect of binational observational study. There are 27 Australian and New Zealand ICUs that deliver ECMO services that are involved in the registry. So the data is aligned with the adult patient database and the ELSO registry data that's already collected. But a site survey is undertaken each year to identify specific clinical practice guidelines, complication reporting, resource utilization, and training practices at each of the sites involved in the registry. One of the great things about this is the ability to embed other trials within the registry to answer new investigator-initiated, hypothesis-driven clinical questions. And currently, there are three nested studies within Excel. Blender I'll talk about next. OBLEX is an international observational study of blood management for ECMO patients that some of you might be involved in. And ECMO Energy is a single center observational study exploring the feasibility of measuring energy expenditure in patients on VA ECMO using indirect calorimetry. So currently, this is now updated. We've enrolled 182 patients as of this morning out of their target of 525. And there's still some sites to come on board. So one of the nested sub-studies within the Excel registry is the Blender study led by Dave Pilcher, which is looking at a conservative oxygen strategy as compared to a liberal oxygen strategy in 300 patients on VA ECMO. So again, this is a registry-based randomized control trial. And what we do is we use the data collected from the Excel registry and the adult patient database with follow-up outcome assessments being performed through their registry as well. So up and running, starting to recruit with more sites coming on board. Now, there's a name for a trial, Megarox. And this follows on from the ICUROX trial that many of you will have seen published in New England Journal last year, which randomly assigned 1,000 mechanically ventilated adults to conservative or usual oxygen therapy. Now, the study found no significant difference in the number of ventilator-free days. But it is possible that the trial was not actually large enough to detect a clinical difference. And so in theory, ICUROX possibly restores equipoise about oxygen therapy in ICU. But it's not definitive. Post-hoc analyses found that the subgroup of patients with ischemic hypoxic encephalopathy were found to benefit from the conservative oxygen strategy with lower mortality and better neurological outcome at day 180, while patients who had other acute brain pathologies or sepsis appeared to do better with usual care oxygen. So this is all hypothesis generating and the basis for further research. So based on the data in the ICUROX trial, there's a 46% chance that conservative oxygen therapy targets actually increase absolute mortality by more than 1 and 1 half percentage points, and a 19.3% chance that conservative oxygen therapy targets decrease absolute mortality by more than 1.5% percentage points when compared to liberal oxygen therapy. So based on the control group mortality of 29%, which was what was found in ICU rocks, a sample size of 38,000 provides a 90% power to detect an absolute mortality difference of 1 and 1.5%. What we've done is increase this to 40,000 because we do like a good challenge, but it also allows for a loss to follow up and a planned adaptive randomization. That's what 40,000 patients looks like, so it's quite a challenge. To answer this, we're going to undertake the Megarocks trial, but this means that we need to enroll around about 200 patients a week. I'll go on in a second and tell you how we're going to do that. But there are some innovative trial features to this, particularly around linkage to existing national ICU registries so that the outcome data don't actually need to be collected at a site level by research coordinators. And response adaptive randomization, which gives trial participants an increased chance of being assigned to the best performing group as time goes on. So it is a randomized trial, but unless observed mortality rates based on available data are equal, the randomization won't be 1 to 1. It will instead be 1.05 to 1 within each of the subgroups. And on average, this kind of means for patients that being in the trial is actually better than being out of the trial. So going back, how do we achieve 40,000 patients enrolled? It needs to be really easy to enroll, consent, implement, and collect the data. We can make this easy to enroll. The only patients who will be excluded pretty much are those where enrollment is not considered to be in the patient's best interest. In some jurisdictions, a waiver of consent may be possible, and in others, an opt-out consent model will be used where information is provided to the patients. The study compares two approaches to oxygen therapy, which were tested in the ICU ROCS trial. And we know that we can implement this fairly easily at the bedside. The data is easy to collect. This is already collected through our adult patient database as the primary endpoint is in hospital, four-cause mortality up to 90 days. And MEGA-ROCS is not just one trial. It includes nested trials based on post-hoc analyses of the ICU ROCS trial. So there will be MEGA-ROCS sepsis, MEGA-ROCS HIE, and MEGA-ROCS acute brain pathologies as well. And finally, an invitation to come and join us down under. We have a couple of meetings each year. The first is actually in a couple of weeks' time in sunny Queensland in Australia. Anyone is welcome to register and attend. This is our annual scientific meeting, which is a three-day meeting plus a one-day research coordinator meeting. It's lovely and warm up there at this time of the year. And then we also have a second winter meeting, which is held in New Zealand, which is even better than Australia, down on the South Island. And that's being held in August this year for a couple of days and involves a break in the middle of the day for a bit of skiing as well. So anyone is more than welcome to come and attend. We'd love to see you there and to be able to share some of our experience with you. So thank you. Thank you. Thank you, Professor Park. I hope that sets a high bar for the future coming speakers where we have invitations to exotic locations to participate. Our next speaker is Dr. Gong. She is incoming chair of the Kirkland Discovery Network. And she is here to present on future and upcoming trials from Discovery. Thank you. Thank you so much. It's a great pleasure today to actually talk with you a little bit about some of the developments that has been happening within the Discovery Network. So just in terms of disclosure, I have some grant disclosure, but no commercial interest. So the Discovery Network is actually a relatively new entity within Society of Critical Care Medicine. In fact, actually, the development of the Discovery Network was first announced about two years ago at SACM in Hawaii in January 2017. And the network was founded with the goal to increase collaborative research to improve outcomes for critically ill and injured patients, and to use the SACM's existing broad base of programs to disseminate the findings into practice. So what I'm hoping to do over the next few minutes is to describe for you some of the studies that have been generated over the last two years in the Discovery Network, as well as actually some of the resources that the Discovery Network has to facilitate your research and your investigations going forward. So the first that I want to talk a little bit about is actually the volume chaser, which is actually a good example of how things actually can develop, be executed, and implemented within the Discovery Network. The volume chaser study is a multi-center observational study examining the practice variations in fluid administration and vasopressor use in shock, something that we deal with on a daily basis in the ICU. And it involves, actually, a collaboration between the US Critical Illness and Injury Trials Group, which have preexisted since 2008, of critical care physicians and investigators, as well as an existing trials group within the Society of Critical Care Medicine. The Critical Care Pharmacotherapy Trials Network Group. And this was actually a natural synergy between something that the investigators were interested in and used it, as well as something that the CCPTN were also interested. The specific aims of the study was to characterize the use of physiological measures, static or dynamic measures, versus clinical findings to determine fluid responsiveness and vasopressor use. Two, to determine whether the use of physiological measures is associated with decreased fluid administration and earlier use of vasopressors. And three, to explore using a propensity score analysis whether the use of physiologic is associated with organ failure and survival. So to kind of give you an idea of the evolution of how this happened, it started off with an Oracle meeting in January of 2017, in which the Discovery Network meeting was first announced, but also actually gave a chance to investigators to propose studies to be done. And at that first meeting in January of 2017, Dr. Chen actually proposed a study looking at this issue of physiological assessment for volume resuscitation. During that same study, actually, during that same session, Dr. Russell Roberts also had proposed a study looking at vasopressors. And as you can imagine, there was actually natural synergy and discussions between the group. And then things actually happened very rapidly at that point. Within two months, actually, there was a first webinar talking about the volume, the fluid resuscitation aspect of the study. But within a month of that, Dr. Russell Roberts, as well as Dr. Chen, had collaborated and basically merged the protocols together into VolumeChaser to look at both fluid resuscitation as well as vasopressor therapy. And then it became a true partnership going forward. Within five months, actually, of that collaboration, IRB was obtained, electronic health records, electronic case report forms were all developed, training sessions were already started, and study enrollment began in September of 2017. So that by the time of the next SACM meeting in February 2018, study enrollment had already completed from 34 sites within the United States as well as outside, enrolling over 1,600 patients into the study. By October of 2019, two manuscripts has already been submitted to Critical Care Medicine. And we're now actually been invited to revise and submit. And that is actually ongoing right now in January of 2020. And I think this gives you an example of actually how studies can be proposed, generated, executed, and rapidly escalated in this. In addition, these studies provide an avenue for other investigations. So a mechanism has been developed within the Discovery Network to create a publication committee in which people who participate within these projects can propose ancillary studies off of the primary data set. And as you can see here, there's been actually 12 ancillary studies that have been proposed and accepted. The data has been released to all of these investigators. And in fact, actually, one of the studies looking at timing of initiation of invasive mechanical ventilation and the effects on outcomes for patients in shock, led by Dr. Golal and Dr. Matthews over at Mount Sinai, has been analyzed, submitted, and actually was, we were just notified that they were accepted for an oral mini-symposium at ATS following in this May. And only about 3% of the abstracts are actually accepted for that mini-symposium. So that's a great achievement on their part. Another study is the VICTA study, which you may have heard about from last year. This has to do with something that has generated a lot of news recently. And that is the issue of vitamin C, thiamine, steroids, and the sepsis. And this is a multi-center, randomized control trial, randomizing patients to high-dose vitamin C every six hours, thiamine, and hydrocortisone for four days or until ICU discharge versus a placebo. The outcome is a vasopressor and ventilator free days. And as of July of this year, the study has been completed with 501 patients enrolled within 43 sites. And this was, again, a study that was proposed at last year's SACM and was proposed, executed, and enrolled within that time frame. Other upcoming trials has to do with, for example, in this one, oral mitodrine and early sepsis. So mitodrine, as you know, is an oral alpha-1 agonist. And many of us have been using mitodrine in our patients with low-dose pressor requirements to help them get them off or borderline blood pressure. And in fact, if you look at the use of mitodrine in the ICUs, there's been a steady increase in the use of mitodrine in the ICU. An observational study looking at actually what happens to pressor requirements in patients before they start mitodrine and then 24 hours afterwards shows that the blood pressure is maybe a little bit better. But the amount of pressors needed at 24 hours is significantly lower after starting in mitodrine with relatively few side effects, mostly actually in terms of bradycardia. The problem, however, it's not clear whether or not these pressors requirement would have gone down anyway after 24 hours or whether how much of the effect is actually due to the mitodrine. So Dr. Ogiegajek and his colleagues have embarked on a pilot study looking at oral mitodrine and early sepsis, where they aim to randomize patients with sepsis defined as actually, you know, suspicion of infections and need for vasopressor use or at least two blood pressures with a MAP less than 70 and randomize them to either oral mitodrine or placebo. And the goal there is to then see actually with this randomized prospective clinical trial whether or not oral mitodrine does decrease the need of vasopressors. Another trial that I want to talk about is the arrest pneumonia. And this is another study that actually had its genesis as a proposal within the Discovery Network by Dr. Joseph Leavitt and Dr. Amir Festig. And it was proposed, it was actually suggestions and revisions were made and that ultimately, and they got endorsed within the Discovery Network as a trial worthy of doing. And this ultimately actually led to their funding from the NHLBI. And the arrest pneumonia is a multi-centered, double-blind phase three randomized control trial aiming to enroll about 600 patients with severe hypoxemic pneumonia. The objective is to establish the efficacy of early treatment with inhaled cortical steroids with a beta agonist versus a placebo for the prevention of acute respiratory failure. And to identify baseline clinical and biological characteristics to impact the risk of acute respiratory failure due to pneumonia and to see actually whether or not a help dictates variable response to therapy. So patients presenting to the emergency department with severe pneumonia are screened and hopefully actually randomized within 24 hours. And they must be randomized and consented and randomized within 12 hours of meeting the first criteria for study entry. They're then randomized to either five days to podecinone and fumotero versus placebo. And biomarkers are collected at baseline in 48 hours for the second objective to look at biomarkers that might predict risk as well as variable treatment response. The primary response is progression to respiratory failure as defined by either use of high flow nasal cannula or non-invasive ventilation for more than 24 hours or some kind of combination of those type of ventilatory support plus invasive mechanical ventilation for 24 hours. Secondary outcomes includes duration for need for oxygen therapy as well as length of stay and 60 day mortality. Enrollment is to begin in May of 2020 and we look forward to this trial. So, so far what I've described is just a little snippets of the different studies that has come through the Discovery Network over the last two years. And here are actually another list of several of the studies that has come through and that has been endorsed by the Discovery Network. Now, what does it mean to be endorsed and how do these studies go through? Well, these studies have all been presented at one of the investigators meetings that are held by the Discovery Network each year. And there are about three total, one at SCCM, one at ATS and then we also hold a fall meeting at the NIH which is actually really nice and intimate because we oftentimes will have the NHLBI officers as well as the other NIH officers at the meeting as well. And it presents an opportunity to network with other investigators, to learn about the discovery programs, for investigators to present proposals for review and feedback and for recruiting sites. And usually the proposals that have the highest ranking from the review committee as well as the presentation will be given a letter of support and endorsement by which they use to then apply for funding. And so far that has been very well received by the NIH officers and successful so far. But in addition to these investigators meeting, the Discovery Network has been actively working to try to provide more resources to the SCCM members for their investigations. And that involves actually both a data coordinating center as well as data sets available. So if you go to the website on the Discovery Network, it will list some of these things. So regards to the data coordinating center, this is actually relatively new in the past year or so. And this is a data coordinating center led by Dr. Douglas Linsdale who is a professor of biomedical informatics, biostatistics and clinical translational science at the University of Pittsburgh. And it is supported by SCCM data administrator, project managers, as well as REDCap administrators. What they can provide for studies and investigators as they're applying for their grant proposal is administrative staff to help do some of the regulatory aspects of the trial, as well as an independent central institutional real board. And as many of you know, who are applying for NIH studies, multi-center studies now require a centralized IRB. In addition, there is a REDCap cloud for web-based electronic data collection as well as administrators to assign access and procedures in place to ensure data transfer in a HICPA compliant manner between sites and the clinical coordinating center. The data coordinating center for the discovery aims to help investigators translate questions into appropriate study design and analysis strategy to help them in their submission for grant proposals to the funding agencies. As part of that, they will help calculate sample size, power estimates, develop the case report forms, manage the data, as well as actually head the analysis, standard and novel, and methods for dissemination. They will start aggregating the DSMB as well as also the data required for recruitment and safety reports to the DSMB and other committees, as well as actually provide oversight for adverse event reporting and any other logistical support as needed for specific RFAs. We've already had one study that, since it only started this past year, that have been submitted to the NIH. Look, this is a bio-cast study by Dr. Ogi Gajic using the discovery network as the data coordinating center. Unfortunately, we didn't get funded for this one, but we hope to actually go in again on another mechanism. Now, in addition to the data coordinating center, you can see there, there's also data set available. And that's actually to take advantage of another resource that SCCM has. SCCM has been a leader in implementing a number of clinical initiatives. And as such, actually, those data is available for investigators. If you go to the website on the data set, you'll find actually that currently there are two data sets made available for investigators. Data from both the adult and pediatric population for the ICU liberation initiative, as well as actually data from a surviving sepsis campaign. And if you click on that, there's an application form that you can fill out to be able to have access to that data. In addition, discovery does generate grants for investigators. And since 2008, discovery has given out $235,000 in grants. Most recently, the grant was given to Brian, Dr. Brian Verisco from the Cincinnati Children's Hospital to look at a multi-omic approach to identifying pediatric ARDS endotypes. Another one had gone to Dr. Amelia Barwise from Mayo Clinic, who was doing a nested observational cohort to evaluate diagnostic error and delay in the critically ill. And actually yesterday was our discovery network meeting. And she very nicely actually presented the results and update from this grant that she had gotten last year. Previously, Dr. Lauren Vasco received a grant for preparing families for process of shared decision-making during ICU family meeting. And Dr. Sam received a grant looking at breathing efforts in ARDS. So in summary, actually, the discovery network, even though it's only actually been formed and announced two years ago, has been steadily working at promoting the research initiatives within the Society of Critical Care Medicine and to provide resources for additional research investigations. So I invite all of you to actually visit the discovery network website. And on there, you'll be able to see, actually, the upcoming investigators meeting, programs that has been endorsed and projects, as well as actually ways of submitting your own proposal for review. Other resources, which include, say, the data sets, as well as the Clinical Coordinating Center, as well as publications that has been generated as part of these various proposals that has been endorsed by the discovery network. And with that, I want to thank all of you for your attention. Thank you. Thank you, Dr. Gong. With that, we will transition to our next speaker, representing the Canadian Critical Care Trials Group. We have Bram Rockworth, studies that will change practice within the next five years. Thank you. Good morning, everyone. My pleasure to be representing the Canadian Critical Care Trials Group here today, discussing some of our ongoing research, but also a bit around our approach as well. I sit on the executive. They had asked perhaps some of the more senior members who were unavailable, and fortunately, I was, so very appreciative for the opportunity to represent the group here today. In terms of background, the trials group was formulated in 1989, and it was actually a returning graduate student clinician who had recently finished her training at Stanford, who came up with the ideas for the first couple of projects that the trials group undertook. And in retrospect, I think that this was a good choice as Deborah Cook had come with the ideas for two trials looking at the role of stress ulcer prophylaxis, which ended up turning into two New England Journal trial publications, and really formed a lot of the framework for the ongoing success that the trials group has experienced. To date, approximately 350 Canadian critical care professionals representing 60 intensive cares across the country. And probably one of our most proud attributes is the inclusion of a multidisciplinary membership, including not just doctors, but allied healthcare, nurses, research coordinators, basic scientists, patients, and family partners as well. In terms of vision, the goal is to advance the care of our sickest patients through the excellence of research. And this is accomplished through a few different values and representations, including patient-centered focus, and I'll talk a little bit more about this shortly. Integrity, innovation, and collaboration, both across the country, as well as with other trials groups and organizations worldwide. This iconic photo is Lake Louise in Alberta, and it's relevant because it's the site of one of our thrice annual meetings. We meet three times a year as trials group. We meet in the wintertime in the Rockies, providing a nice avenue to skiing as well. We meet in November around the Canadian Critical Care Forum, and then in the springtime, somewhere in the eastern portion of the country. And I think one of the integral components to the success of trials group is not just the research productivity, the constructive collaboration that occurs during the research meetings, but the ample time for networking and discussion that happens outside of the formal research setting as well. And you can see that this is one of our sort of normal schedules during one of our meetings, with usually meeting time in the morning, we start early, but ample time in the afternoon, we start early, but ample time during the day to explore perhaps the ski slopes, hiking trails, or whatever opportunities exist wherever we're meeting. And it's that networking and that discussion that happens informally that sometimes just as crucial as what happens behind meeting doors. And you'll also notice that most days end with some social activity, whether it be karaoke night, perhaps organized dinner, or socializing otherwise. And I think, again, this has certainly been crucial to our success. We're currently on our fifth chair. Rob Fowler recently took over from Paul A. Baer just last year in the relatively short history that we've existed. And not only do we include the general trials group, but there's a couple of subcommittees under as well, including a translational biology group that meets usually just before the trials group and then along with us, as well as a research coordinator group. And as many of you know who do clinical research, research coordinators are monumental to the success of both research and our research consortium. And it's very excitingly, they've actually started to produce research in their own event in terms of primary publications around studies with consent and enrollment, and very excited. In terms of accomplishments, and some of these numbers might be a little bit out of date, almost $130 million Canadian in peer-reviewed grants, over $40 million from CIHR, which is our NIH equivalent, 17 publications in New England Journal, lots of others in other major journals, and over 50 multicenter projects that are currently ongoing, and some of which I will tell you about shortly. Current membership, and I highlighted this already, is about 120 physicians, but we value the input of non-MDs as well, and have a number of PhD ICU trainees, as well as research coordinators and other health professionals that make up our membership. In terms of things that we're proud of from an approach perspective, is that I would say the patient and family input to research programs is something that we like to highlight. And there's a separate subcommittee specifically dedicated to this, led by Sylvie. Sylvie is not a clinician. She had a child that was afflicted with sepsis, who survived, and she's turned into an incredible patient advocate, and has done incredible work at the trials group, providing input into research programs, input into our mission as a society. It's been quite unbelievable. I think one of the other things that we're most proud of is our mentorship of junior investigators, and I've definitely benefited from this myself. This is a very supportive environment, a very inclusive environment, and this article highlights both two of our junior, now moving towards middle career investigators, but also two of our non-MD investigators as well. Michelle Ko, who's a very successful Canadian research chair and physiotherapist, leading the cycle trial, and Mark Duffett is a clinical pharmacologist in critical care at McMaster, equally successful, and has taken advantage of the mentorship opportunities that exist at trials group. The mindset around trials group is a programmatic approach to research. We start with a clinical question, usually developed based on clinical care that you might have generated well at the bedside. You involve stakeholders in perfecting your clinical question, and organizing it, and developing the best approach to answering it, including input from bedside clinical staff, research coordinators, biostatisticians, and very importantly, patients and families, and we translate that again into a program of research. The trials group approach is not to approach CIHR asking for funding for the definitive randomized control trial right off the hop, but rather work through the process, build the bricks, and starting with a systematic review, what's the landscape right now around this research question? Perhaps going from there to a survey of current attitudes and practices, moving up with observational studies around your area or question of interest, and finally working through feasibility pilot work before engaging in the definitive randomized control trial. And although we don't stick to this all the time, it's definitely sort of this suggested approach to best dealing with research questions, and it's the approach that I've taken as well, and you see, as you incrementally build your program, the adequate refinement in your research question that occurs, and it really sort of best positions you for successfully addressing things, as well as being successful with funding. Does anyone ever do this? My own research program is looking at the question of different intravenous fluids in septic shock, specifically comparing normal saline versus Ringer's lactate in patients with septic shock, and did follow through this programmatic approach starting with a systematic review. From there, we performed a network meta-analysis, did some pilot feasibility work at two centers using local funding, was able to transition that local funding to provincial funding, which provided an expanded trial at 10 provincial sites, and just recently was funded for a large-scale definitive RCT being able to expand up to 1,100 patients at 25 centers worldwide. And I'm 100% convinced that this incremental success in funding was only possible from those bricks that were built along the way, the program that was built from the bottom up. In terms of my specific research program, I know what a lot of you are thinking. This is a very en vogue question. Lots of groups, including Flavia's and the Bricknet group, as well as the Australian group, and Rachel's with ANZIGS are addressing similar research questions. There's a couple of unique aspects to FISH, my own research program, around fluids. One, we are only looking at patients with sepsis and septic shock specifically, so this is a very sick subgroup of patients, high baseline risk of mortality, and we're able to capture these patients early using some of our tactics that we avoid upfront fluid contamination. It's done at an individual patient level. And some of this has translated into a relatively large volume of study fluid administered. And you can see that from some of the previous studies, it seems in fluid trials, one, two, three liters of fluid is sort of normal for volume of fluid administered as part of a fluid trial. At least in the preliminary patients in FISH, we've been around the six, seven liters of fluid administered. Now, this isn't only in the first day or couple of days the fluid is administered until ICU discharge death or 30 days. So some of this fluid administration occurs throughout the ICU admission, but there's no doubt that a lot of it is upfront in the first 24 or 48 hours. So a number of trials that are hopefully addressing this important research question, and we should have some more data around optimal fluid for resuscitation in the coming years. In terms of FISH, we're using that incremental funding that we just were able to achieve. We're in expansion mode right now, looking at adding sites, enrolling more patients. Our total sample size will be 1,100 patients. We've randomized 200 to date and hope to be done within the next two to three years. Now that you've had a little bit of the background and the approach in terms of trials group, highlight a few of our studies that are currently ongoing or close to completion and summarize them next here. Many of you are probably familiar with START-AKI, trial led by Sean Bagshaw and Ron Wald from Edmonton and Toronto respectively, looking at the timing of renal replacement therapy in patients in the ICU with acute kidney injury. There's been a couple of smaller randomized control trials addressing this question. START-AKI will be the largest and really an incredible piece of work when you look at the collaboration that Sean and Ron were able to develop. And I think I'll use each of the trials that we'll highlight to perhaps illustrate one of the amazing aspects of each of these randomized control trials and for this one certainly I think collaboration worldwide is one of the key features. They were able to operationalize this trial at 164 sites which seems amazing. I have trouble managing my own trial at 10 sites and looking to 25 sites and I can't imagine the hurdles and operational headaches with expanding a trial so widely. Very excitingly they've finished enrollment and currently finalizing statistical analysis and we should expect results from StartAKI soon within the next couple of months. Similarly Prospect has recently finished enrollment. This is Deborah Cook's most recent trial looking at probiotics specifically lactobacillus versus placebo in mechanically ventilated adult patients. They're comparing this versus placebo and looking at the effect on nosocomial infections. Specifically the primary outcome is ventilator-associated pneumonia but also looking at C. diff rates, bacteremia rates, this sort of thing. They enrolled over 2,500 patients, 44 ICUs worldwide, Canada, the US and Saudi Arabia and similarly just in the database cleaning stage and hopefully we should have results around this quite soon. An interesting research question around selective gut decontamination. Again a trial that relies on collaboration specifically with our Australian and ANZIGS New Zealand group as well. Led by Dr. Cuthbertson, Brian Cuthbertson out of Sunnybrook and at least the Canadian arm and a great example of persistence. This has been a trial that Brian has felt strongly about pushing forward with for a number of years and despite unfortunate news earlier on in terms of funding decisions fought forward and fought forward and was successful with at least Canadian funding just in the last couple of years. So although I believe ANZIGS is well on their way to enrolling in this trial we're just getting going in Canada and look forward to some further data addressing this idea of selective gut decontamination. I think all of us sort of surprised on some of the early mostly Dutch data that showed benefit of these antibacterial and antifungal regimes when rolled out to all of our ICU patients and I think it will be very important to address this in a wide scale international trial to see if that benefit translates whether it's generalizable. So this one's still in the early stages. One of the things I've talked about already at trials group is diversity and diversity also translates into pediatric and adult groups and different than other trials group perhaps although I don't know for certain is that we don't separate two streams of adults and pediatrics but rather we all meet in the same room together. We offer input from an adult perspective onto the pediatric trials and vice versa from a pediatric to an adult trials and this is one of our pediatric investigators not the investigators not pediatric but the patients are is Kusum Menon looking at the role of hydrocortisone in septic shock in children and again a great example of persistence. Kusum pushed forward with this through a couple of difficult decisions and has been recently successful with wide-scale funding. Again also a great example of collaboration with the American trials group and is now going to be looking at enrolling a thousand thirty-two children with septic shock to see whether steroids have a role or not and numbers in that range in pediatric trials is unbelievable. Much more difficult to enroll in pediatric trials than adult trials. We don't only support randomized control trials but also observational work multi-center observational work and this is probably one of our most successful observational research programs from trials group very successfully led by Margaret Harridge in Toronto looking at recovery after critical illness and with the increasing focus that find patients survive but what about all the comorbidities and morbidity that exists after one survives their ICU stay and this has led already to a number this research program has led already to a number of New England Journal publications and at this point Dr. Harridge is looking at issues around navigators post ICU navigators and how they interact with physiatry and rehab including psychologists and other allied healthcare teams so very very successful non RCT research program. Cycle which is another non MD led research program by Michelle Koh who's a Canadian research chair physiotherapist based out of my own center in Hamilton looking at in bed cycling versus routine physiotherapy and mechanically ventilated patients always very very dramatic to see these patients mechanically ventilated you wheel the bicycle to the end of the bed strap their legs in and if they're able to actively cycle they do if they're not able to the machine will passively cycle them as well and looking at functional outcomes at one week one month and longer-term outcomes as well an incredible research program and this is one that's very very popular with patients and families the consent rates are almost a hundred percent patients and families are always enthusiastic to participate and it is an open-label trial always disappointed if they end up in in the routine physiotherapy arm. Translational work is is integral and this research program is a nice mix of translational and clinical work led by Laurel and McIntyre in Ottawa looking at the role of mesenchymal stem cells in septic shock she's done some early phase one work looking at safety dose finding and has now moved forward with a phase two trial looking at efficacy for stem cells in the setting of septic shock. Only a few more another one from the pediatric perspective is the squeeze trial led by Melissa Parker also at McMaster and building on the work done by Kathy Maitland looking at whether a fluid sparing strategy as compared to usual care is beneficial to children with septic shock and perhaps this idea of maybe earlier pressers more aggressive use of pressers and less zealous fluid administration could be beneficial. She is well funded now by our Canadian Institute of Health Research and is well on her way to enrollment of her targeted sample size. We have our own version we've heard of a couple of the other versions of vitamin C trials we have our own version the trials group the love it trial led by Francois Lamontagne and Neil Adhikari looking at specifically the role of vitamin C in septic shock so rather than the cocktail including thiamine and hydrocortisone the love it trial is only looking at high-dose vitamin C in septic shock looking to enroll 800 patients which would be the largest vitamin C trial done to date. I think the last time I checked we're enrolling at my own center there around four or five hundred patients randomized hoping to be done sometime next year. John Marshall who many of you know has collaborated very nicely with the Irish trials group and John Silversides and performing randomized controlled trial looking at active or protocolized de-resuscitation after the resuscitative phase in sepsis and looking to see whether this protocolized administration of diuretics perhaps ultra filtration is beneficial as compared to usual care. I think this was the last one another pediatric trial vitalize led by Dara McNally looking at whether vitamin D supplementation in critically ill children is beneficial we have some data recently in adults but looking to see whether this translates as well. He has also funding from CHR targeting a sample size of around 800 patients and is well on his way to achieving that. Tried to pick a few of our ongoing trials that I think will be impactful over the next five years hopefully it highlights again the key components from trials group in terms of diversity patient and family engagement fostering of junior and young investigators and I think that this is reflected in in the the work that we accomplish and very much appreciate your time and interest. Thank you. Thank you Brian. We have our final speaker coming up and after our final speaker I'll ask the panelists to congregate towards the stage to take a brief question and answer session. With that we have our next speaker Dr. Hassanal Dorsey he is a substituting for Dr. Yassin Al-Rabi who had a family emergency and presenting here from on behalf of the Saudi critical care trials group. Thank you very much. So I'll be presenting on behalf of Dr. Yassin Al-Rabi who could not come today because of a family emergency and I'll be presenting about maybe a different a bit different journey shorter journey but ambitious and I'm waiting for my slides. So obviously I come from Saudi Arabia maybe I'm not sure if all of you know about Saudi Arabia so Saudi Arabia so I control so Saudi Arabia is a country in the Middle East it's in Asia it is a bit large country more than 2 million square kilometer in surface area the population is around 34 millions it is quickly changing country with especially in the last decade so the critical care research in Saudi Arabia before the Saudi critical care trials group was based on individual efforts mainly observational studies and were also single-centered randomness control trials and also some investigators were part of international randomness control trials. Then the there was formation of the Saudi critical care trials group which was developed around five six years ago to promote high-impact critical care research in Saudi Arabia and to facilitate collaboration among researchers in Saudi Arabia as well as international international researchers. It is under the Saudi critical care society and it's founded and chaired by Dr. Yassin Arabi. I would like to point out to this landmark trial which was done before the formation of the Saudi critical care trial group however I think it had it had a big role in the formation of the trials group and it is the PERMET trial. The PERMET trial was the first multi-center international randomness control trial that had its PI who was Dr. Yassin Arabi from Saudi Arabia. So it was done in seven centers two centers from Saudi Arabia and five centers from Canada. It was funded by our research center in Riyadh and it randomized almost 900 patients to two groups permissive underfeeding and or standard feeding and the study did not show any difference in 90-day mortality which was the primary outcome. This study was published in the New England Journal of Medicine in 2015. Post hoc analysis of the trial showed no difference in mortality between higher protein intake versus lower protein intake. However if you look at the numbers the protein intake in the trial was moderate around 70% of requirement in both groups and there's a belief that protein intake or higher protein intake is beneficial to ICU patients especially if given later during the critical illness and so hence we have the trial which is replenished. So this trial has not started yet the multi-center one so it is replacing protein via enteral nutrition in a stepwise approach in critically ill patients and it will compare high enteral protein ranging giving protein between 2 and 2.4 grams per kilogram per day versus lower protein around 1.2 grams per kilogram per day. Starting day number five of ICU stay as I said because there is data that giving high protein in the early phase of critical illness is associated with worse outcomes. The primary outcome of this trial will be all-cause 90-day mortality. We have recently finished a pilot feasibility trial at our hospital King Abdulaziz Medical City in Riyadh and we have enrolled 40 patients and the study is feasible and the data are being analyzed. We don't have the results of this trial yet. So the replenished trial will be a multi-center and mass control trial. It will happen in 19 sites from four countries. Most of the sites will be from Saudi Arabia but we have sites from Denmark, Belgium and India. We have IRB approval and the plan is to start this trial later on this year probably in June 2020. The methods of this trial there are going to be a pre-randomization so the intervention is going to start on day number five. So between day number one and day number four we will we're going to have will gather nutritional data about patients and the nutritional support will be given by the treating team. After enrollment patients will receive modest doses of protein between 0.5 to 0.80 gram per day from the feeding formula. On day number five the patients will be randomized into two groups. The first group is the replenished protein group and this is the high protein group around 2 to 2.4 grams per kilogram per day and the other group will be standard protein a group taking between 0.8 to 1.2 grams per kilogram per day. And in the replenished group there is going to be supplementation of protein by intermittently through the tube feeding tube. So this trial probably is going to take a few years to be done to finish and then hopefully it will give us more information about this nutrition topic. Now Saudi Arabia was hit by the Middle East respiratory Middle East respiratory syndrome MERS coronavirus infection. The first case was identified in Saudi Arabia in 2012. After that there were lots of cases of MERS-CoV and so far we have almost 2,500 cases of MERS-CoV in 27 countries but the vast majority of cases were in Saudi Arabia. And since 2012 there were several hospital outbreaks of MERS-CoV in hospitals and my hospital also had an outbreak in summer of 2015 and so it was an adversity but I think it played a big role in the formation of the Saudi critical care trial group as health care providers and researchers started to collaborate among each other and this led actually to the publication of several studies about MERS-CoV and there was collaboration between many many clinicians on this disease. This led to the next trial I'm going to talk about which is the medical trial and the medical trial is a multi-center and the most placebo-controlled double-blind trial. It's going to compare the use of lopinavir in combination with ritonavir which are antiretroviral medications with recombinant interferon beta-1b versus placebo. The trial has started around three years ago. The number of cases recently of MERS-CoV cases has decreased significantly in Saudi Arabia so this is why recruitment has been a bit slow. There was one interim analysis done at 34 patients and the data, there was recommendation to continue enrollment of the study. So far 87 patients have been recruited from 16 sites in Saudi Arabia and the second interim analysis is expected to occur soon. The expected sample size is 114 patients and we expect to finish the trial in six to twelve months and I think the results of this trial may be important especially with the current outbreak of the new corona in China and other parts of the world. Related to the same issue, viral infections, MERS-CoV and so on, so there is this study which is not a trial, it's called VERIFY which is a registry and the primary objective of the registry is to examine the virological etiology of severe acute respiratory infection among patients who are intubated in Saudi Arabia using PCR and metagenomic techniques. It has other objectives which include to identify the risk factors for disease progression and organ failure, to collect data and determine types and differences in current clinical management of such patients and also we're going to store samples from these patients in our research center, it's K-Mark, it's called K-Mark for future research including storing cell fraction and whole body, whole blood for more testing, genomic testing. Now we go to another trial that is the result of the Saudi Critical Care Trials Group, it's called the PREVENT trial. This trial was published in the New Age of Medicine mid of last year, so less than a year ago, and it compared the use of intermittent pneumatic compression devices plus pharmacological prophylaxis for DVT versus pharmacological thromboprophylaxis alone and in this trial there were surveillance for DVT using Doppler ultrasound on admission and twice weekly. In this trial DVT occurred in 3.9% in the group that had had adjunctive use of pneumatic compression devices in addition to the pharmacological thromboprophylaxis compared to 4.2% DVT incidence in the group that got pharmacological prophylaxis alone and there was no significant difference. So a pre-planned analysis from this trial looked into the issue of surveillance using Doppler lower extremity for DVT versus no surveillance. So in this the first group included the enrolled patients in the trial and in the second group included patients who were eligible to be enrolled but they were not enrolled for different reasons. So this is a pre-planned analysis and consent was taken from these patients or their next of kin to collect additional data on them. And so looking at the value of surveillance on outcomes of these patients. So the analysis, so this will be published soon in the intensive care medicine journal and in this study surveillance was shared with a decrease in 90-day mortality with adjusted hazard ratio of 0.75 and significant. There was early diagnosis of DVT in the surveillance group. So the diagnosis of DVT occurred on a median of four days compared to 20 days in the non-surveillance group and there was also earlier diagnosis of PE in the surveillance group and there was an increase in diagnosis of DVT with adjusted hazard ratio of 5.5. But there was no increase in diagnosis of pulmonary embolism in this trial. So this led to the trial called DETECT. So diagnosis DVT or diagnosing DVT early in critical patients. So this trial will assess the superiority of surveillance ultrasonography for lower extremity DVT versus standard practice on 90-day mortality. So it will be a prospective multi-center parallel group randomized trial in ICU patients and the patients will be randomized into twice weekly bilateral lower extremity ultrasound, Doppler ultrasound versus standard of care. The sample size will be 1714 patients. So 1714 patients and it is expected to be happening in 20 sites. Most of them will be in Saudi Arabia and in four countries. The plan is to start the study in July 2020 but I'm not sure about this date. I expect it's going to be started later than that. So we're not only doing randomized control trials. We are doing also quality improvement projects. So this is called NASAM which is National Approach to Standardize and Improve Mechanical Ventilation. So it's a national collaborative quality improvement project in Saudi Arabia aiming to improve the care of mechanically ventilated patients and reduce complication associated with mechanical ventilation. So this project was launched around one year ago and it is being done at 70 and 73 ICUs in 47 hospitals in 27 cities in Saudi Arabia. And so far we have more than 70,000 patient days collected data and already entered. And this project utilizes different approaches. So it involved creation of comprehensive unit-based safety program teams, implementation of evidence-based bundles of care for patients who are intubated. It's employing minimal data collection unlike the entry, real-time benchmarking, webinars, training and coaching and patient safety culture surveys. The trials group also has been involved in training health care providers to increase and to build capacity for doing research. So we have been doing basic research courses, basic clinical research coordinator courses, and these courses are done over two days. And we have international and national instructors and these are the flyers for the courses. And as you've seen, Dr. Park is one of the instructors as well as Dr. Shea McGinnis. So I think they have visited us so far twice, maybe more than that, and they are coming in two weeks for the third course. I think basic research course and the basic, I think, clinical research coordinator course. Other activities by the trials group include having research days, and so far we have done five research days. And during these research days, health care providers, physicians usually have pharmacology, clinical pharmacists also coming and presenting proposals, research proposals, and research ideas. And these days, research days, have resulted in multiple research projects that are being done. To my knowledge, there is one ongoing single center trial that is being done about sedation, about using ketamine infusion in ICU patients. And we have also several observational studies that have been, that are ongoing and resulted from these research days. Also, the trials group is providing mentorship of research projects for ICU fellows and residents. In conclusion, I think I'm providing a bit different, maybe different perspective than the other experiences. So I believe that the, our trials group journey is a good example on capacity building to eventually perform collaborative high-quality research. And as I presented, multiple studies are being conducted, and the results will likely impact our practice of critical care medicine in the near future. Thank you very much. Okay, thank you Dr. Aldorsi. If I may invite the speakers that have presented already to the stage, we can entertain. We have about 20 minutes for question and answers. And naturally, we don't have enough microphones, but certainly we can rotate and hopefully make space for everybody. I think in totality, over the course of the last hour and plus, what we've had the opportunity to see is the spectrum of genesis of critical care trials networks from around the world, and where they are in terms of initiation to actually well-established critical care trials groups. And so there's certainly a wealth of information to be gained from all of us here. So with that, let me open it up to any questions and answers we may have from the audience. If you may politely step to a microphone and introduce yourself, and pose a question, please feel free. Hi, Raquel Bartz from Duke. One of the things that I've noticed sort of worldwide, and this is probably has to do with the payment models actually of other governments, end up allowing for these development of registries and critical care trials groups established within local systems that ultimately get disseminated. How do we overcome this issue in the U.S.? And you know, I'll get some thoughts, hopefully from those who've seen our system from outside the U.S. But you know, just even establishing a registry and beginning to benchmark our outcomes and the way we deliver care within our ICUs, it's really, it's just extraordinarily different across the United States. So Dr. Gong, do you have any thoughts about how we begin to overcome within our local hospital cultures, whether it's a community hospital or it's a academic hospital, to begin to develop systems? Because theoretically, we should be able to answer some of these questions extraordinarily quickly that end up plaguing us here in the U.S. in terms of the way we deliver care. I think that's a really important question, and actually one of the things that I highlighted on this session is actually the success of our international colleagues in building this kind of an infrastructure and platform to be able to easily launch these studies, not only in terms of clinical trials, but in, unfortunately, in instances of pandemics. So there are a couple of encouraging signs, if I can say. Traditionally, the NIH has not been so interested in being able to fund registries and so forth, which makes it inherently difficult for us to create these kind of a multi-center platform. Having said that, though, I do see signs of encouragement on several factors. So for example, actually, the NIH has come more to start appreciating the potential power of linking electronic health record data across different sites, which will allow for more of these kind of registries. Two, they have issued a number of different RFAs, as well as allow for certain studies to plan for a clinical trial using some multi-center observational data first. So one example of that is the NHLBI Petal Network, which was actually designed to run randomized controlled trials in ARDS and in prevention of ARDS and other conditions that may lead to ARDS. They were able, and on scientific reasons, to fund a multi-center study looking at, say, low tidal volume ventilation in patients without ARDS as a way to actually build the data, the preliminary numbers, as well as the feasibility of a larger randomized controlled trial. Some other funding mechanisms, for example, they've had these funding mechanisms for hybrid implementation trials, and what they have built in is that there is a pre-trial period in which they say you can develop, actually, a multi-center observational study to understand what usual care is, what routine care is, as a way of actually launching, using the preliminary studies that are more recent than more historical, to start launching some of these initiatives. And then lastly, there's been increasing discussions on these platform trials that has been discussed by our colleagues here, but I think one of the aspects of these platform trials, and we see that in I-SPY-2, as well as actually in other studies like with the asthma consortium that has been funded up at NIH, they're most successful if there is a pre-existing registry or some kind of a pre-existing multi-center observational epidemiological studies to kind of base some of this stuff. So that's already in existence for some of these things that are not critical care, but are funded by the NIH, and I think that actually as we moved more towards, you know, how we fund these platform trials, if we were going to do them, then it's going to become more of a possibility, because as you have pointed out, realistically, it's very difficult to do with zero support and We do have a very quiet audience, so I'll try to spur one question here with our panelists. It seems increasingly so with the development of multi-center networks from around the world that there's a competition, if you will, for different types of patients, but there's increasing competition amongst each other for collaboration and perhaps even partnership. Certainly an opportunity with incidences like increasing numbers of pandemics could certainly contribute to an opportunity for partnership and collaboration from around the world. Are there efforts to look at resource-intensive versus resource-poor parts of the world, and how different types of interventions can be measured and implemented, and how that could be actually applied to our own practice environments, respectfully, from around the world? So I'll leave that question to whomever would like to. Perhaps Flavio, that might be a good question for you. If you want to use this microphone, please feel free. I'm not sure I understand what you're saying, that you have opportunity to collaborate, but we also have to, how we're going to deal with questions that are resource-poor and resource, yeah. That's a good question, because being from a middle-income country, we have a specific question that are more linked with our needs, like, for instance, impact to MAPA. It's a very specific question, how it accepts attributable mortality in our country, in our settings, and this is going to be an answer that we're going to be only fit for middle-income countries. It's a different reality. So we feel in Bricknet that we have, we need to answer our own questions, but at the same time, we are doing BASICS, which is a twin trial with the PLUS from NSICS, and we're going to answer a question that is needed for all the intensive care community. And I think that this is the way to go. However, Bricknet, for instance, being one of quite successful network in a middle-income country, we discuss inside ourselves how far we can go with collaboration. How can we deal with all this? Because we want to do re-MAPCAP, we are joined re-MAPCAP, we are doing HALO with the Canadians, and we are doing BASICS, not together, but as a twin trial, and we are now doing something with the coronavirus very fast, but in the same way that we need to do our own stuff. So this is quite challenging. I mean, to find the proper balance between our own needs, to answer our own questions, and RENOVATE is going to be a trial for the whole community, but IMPACT MAPA, our platform on multi-resistance, okay, it will fit the high-income countries, not at all. Our profile of multi-resistance is a profile for middle-income countries. It's completely different from what is happening in high-income countries. So I think it's very hard to find a balance between partnership and what we can afford in terms of a young network. I was just going to say, maybe it doesn't address specifically of overcoming that concern around patient numbers and competition related to looking at income-poor regions, but something that we've recently started to operationalize is looking beyond academic centers and more to community-based centers. I feel like this is also an untapped area for patients to include in randomized control trials and improves the generalizability of results. So there's been a big push now to look beyond the traditional academic centers as recruiters and bring in ICUs of 10, 15 patients, if they can identify somebody they can help with ensuring validity of a protocol or drug intervention and data collection, is that this has been a great resource for expanding our capacity in Canada, at least. That's a very good point. Hassan, you had a... I think one of the main challenges in Saudi Arabia is the issue of building capacity. I think we have benefited a lot from participating in studies that were initiated by the Canadian Critical Care Trial Group, U.S. centers, and actually, I think, for sure, in my center, this is how we built our capacity and this is how we learned how to do clinical trials. I think this is what we're trying to do in other centers in Saudi Arabia. I think this is one of the major challenges we have and we have to work on it. And I think by collaborating with other international centers, this is one of the biggest things we have gained from. But I also want to emphasize, actually, what the developed countries can learn from research that are going on in the middle and low-income countries. So within our developed countries, we've been all focused on this sepsis resuscitation compliance, 30 cc's per kilo. But there's been recently several studies that have come out from low-income countries that is suggesting that maybe not, right? And that has actually been, I think, instrumental in shifting some of our thoughts. And now you're hearing about studies in the Canadian Critical Childhood Trial Group, the CLOVER study within the NHLBI Petal Network, where we're now actually challenging this dogma that we used to have within the developed world that we should just pour the fluids into these patients. There's certainly opportunity for bi-directional sort of feedback, where especially with fluid resuscitation and perhaps with pandemic response, where there's possibly greater synergy and opportunity there and overlap. We have time for one final question. My name is Antonio. I would like to know about the experience of the group on dealing with different policies on consent. We are in a partnership with different ethics aspects in different countries. And I've seen different approaches to deal with waiver of consent, ethic, community consultation. And I would like to know the experience of the group on how to deal with critical care research and ethical concerns on consent. We were just talking about this yesterday at the Discovery Network meeting. So probably we all have very different ethical requirements, depending on which country we come from. And even within the ANZAC clinical trials group, because we cover two countries, we have very different consent laws, ethical requirements in each country. So we end up with some trials where in one country they might have a complete waiver of consent, where we might have to get individual patient consent in the other country. Even within states in Australia, it can be different. So it's a constant challenge. And when you're doing multi-center, multinational research, it's a matter of figuring out what goes on in each place. And being able to be guided by the ethics committee in terms of what the right thing to do. Yeah, it's a constant challenge. And there's multiple models. All right. With that, we thank our panelists for their excellent presentations and updates regarding research programs, and certainly programs that you'll be likely to hear more about over the course of the next five years. So a big hands up to them. Thank you.

BRICNET

research network

critical care

high-quality research

collaboration

upcoming studies

BASICS

DONORS

adaptive design trial

high-flow nasal oxygen therapy

non-invasive ventilation

IMPACT-2 MR

sepsis attributable mortality

public hospitals

ethical considerations