 Geto'r ddarm yn y gwneud, a beth eich Skytyrdd yn ydy, yr yw'r cyfnod o'r pethau cyfan. Rydyn ni'n Richard Haynes, mae'n un sy'n hollwch yn Oxydd ar y cyrraedd yma sy'n gweithio ar y cyfrifeddau. Tytul gw'n ddweud eu hwn i bod byddau'r gwaith ar gyfer byddi cyfrwyng hwn, a'r diddlu yn ym mwy dda iawn i fynd ar y cyfrwng mewn cyfrwyng, i fynd i swyddiadau. gyda mi wedi bod, rhan o'n ymgyrch跟我 ag yr oeddfyrddau, ac mae'n ddysgr y tîmnol yn fwyndio'r gwahydiau, mynd i'n meddwl am ddau yn ei bwysig, gwyddiad y Llyfrgell, ac o'n ymgyrch mewn bwysig, a'n ymgyrch gennynnu bod wedi bobl cyllidau, yma, a'r llyfeiddiad yn hyd i'r tîm yn ddiddordeb yn tuadau, i fi wneud y gallu amser, i ni'n ymgyrch i'r cyfrifennidau. A'n gwybod ar gweithio, rwy'n credu ddweud dim iddo. a we're going to talk about some fairly big numbers over the next hour, but I think it's important that we remember that each one of those numbers that we talk about is an individual person with their own story and their own experiences. And for some people watching or listening to this, maybe it didn't always end as well as we would have liked, and we do recognise that, and in fact that's the very reason we do try as light recovery to try and improve the experience for people, and by doing that we can therefore improve public health. I'm delighted to welcome Professor Peter Horby, who's the Professor of Emerging Infectious Diseases here at Oxford University, and one of the chief investigators of the recovery trial, so I'll hand over to Peter to kick us off. Great, thank you very much Richard, and thank you everyone for joining us and I realise we may have participants from across the world, so you know, good morning but also good afternoon and good evening for all of those listening. I'm just going to give a brief introduction to the background of trying to do clinical trials and epidemics and where we've come over the past decade or so. Next slide please. Now, we have frequent epidemics, and the one before this one really was the 2009 swine flu epidemic, and we see very similar messages, so here we saw a call for global action as outbreak spreads. You'll see here some of the rather alarmist headlines in some of the UK newspapers around the swine flu outbreak in 2009. So if we look at what we achieved in terms of clinical trials in 2009, next slide please. We can see that the response wasn't what we would have liked. This graph shows the number of patients that were anticipated to be enrolled in clinical trials of new treatments for influenza. So the bar on the left shows that there were almost 6000 patients that people had the ambition to enroll in clinical trials. And the next bar shows you the actual number of patients enrolled, so far, far fewer, only about one and a half thousand patients. And then the next bar, the third one, the actual patients enrolled where the results were published is tiny, it's negligible. And so what we see is that despite a global pandemic of influenza, which we knew was coming, it's the one outbreak that we were all expecting. We really did not manage to run any good clinical trials of new treatments for influenza. And the upshot of that is that the 10 years afterwards we really don't have any good new treatments for influenza. We did not advance care of patients at all. Next slide please. So those of you who are now familiar with epidemic curves, which we all are over this year. This is what an epidemic curve looks like, but really we had an epidemic curve of ambition in 2009. We had a huge number of ideas, but it did not translate well into protocols into patients and it really translated into zero new evidence. Next slide please. So what we've been trying to do over the last decade really is shift that epidemic curve of ambition so that we're perhaps a bit less ambitious about the number of ideas. But we're much more aggressive in making sure that those ideas do translate into protocols into patients enrolled in trials and to improving care. Whether that's proving things do work or proving things don't work, all of those contribute to improving care. Next slide please. So how did we got on? So this is the Ebola West Africa outbreak of 2014, which you will all have heard about. This was a regional crisis, a huge terrible event actually in West Africa, where we attempted to fast track clinical trials and improve on 2019. And this shows you the epidemic curve of the number of Ebola cases in two of the West African countries with the arrows showing various events. The first arrow shows when our first grant was awarded and several trials were opened with the acronyms you can see there, but the BCV trial was one of the trials that we ran. And it was three, three and a half months from the grant being awarded to the trial being open, which was pretty good improvement compared to the usual time frames of clinical trials, which can be a year or more before you enroll the first patient. That trial then stopped for various reasons. And then we opened a second trial, which is the TKM trial you can see is the last arrow. And it was just 39 days from when we closed the BCV trials opening the TKM trial. So already we'd learned a lot. And we really telescope the timeframe from years to months to just 39 days. But as you can see, it was still quite late in the epidemic. So we really didn't, in that West Africa outbreak, come out with any definitive answers about treatments that work in Ebola. Next slide please. So here we got another outbreak. This time it is the COVID outbreak. The whole world must take action now, similar headlines. Question is, did we improve in our ability to do clinical research? Certainly the quality of the tabloid headlines hasn't improved much, but how has our clinical trials expertise improved? Next slide please. So, obviously the outbreak started in Wuhan in China, and we have ongoing collaborations with partners in China, and the outbreak was first announced on December 30, 2019. And we had our first call on the 2nd of January with our collaborators in China, the little box on the left there. We managed to get a trial up and running in just 20 days, so we improved from 39 days. So the first patient was enrolled in a randomized controlled trial in Wuhan in China just 20 days after the outbreak was announced. That was a real improvement. Next slide please. However, outbreaks are unpredictable, and so you can't always guarantee success even if you're quick. So this shows you what happened to the epidemic curve in Wuhan because of the very aggressive control measures in China. The outbreak was controlled relatively quickly in Wuhan. So although we opened the trial very early on, we still didn't get enough patients to really get a definitive answer in this particular part of the pandemic. Next slide please. So, at this time the outbreak had moved to Europe, and it was clear that we had to shift our focus very quickly from China to Europe, where the epidemic had shifted, and so we had to move with it. And the context of the recovery trial was that experience I've just talked about, and our understanding that there would be a huge clinical challenge. We saw what happened in Wuhan. We saw what was happening in Italy. We knew that we would have overstretched health services, huge time pressures, and a lot of patients that would be quite unwell, many of them elderly. And we also knew there would be huge therapeutic uncertainty. Early on in epidemics there's a lot of candidate drugs suggested that very few of them have any good evidence supporting their use. Next slide please. And, you know, big political pressure to test certain things you'll all have, you know, been following the hydroxychloroquine story where there was huge faith that it worked, but no evidence, and a lot of political pressure to use it. And the only way really to find out whether this is a good drug to use is to do a proper clinical trial and find out. Next slide please. And this goes to the recovery trial, Martin. We'll talk a bit more about this later. It had to be quick, very quick. It had to be big because it was unlikely we would have any single magical drug. And it had to be simple because the health service and the health practitioners, the nurses, the doctors, the pharmacists would be under enormous pressure, so it had to be simple. Next slide please. This now shows the epidemic curve, the early stages of the epidemic curve in the UK. On 10th of March, we spoke with the chief medical officer and explained what we wish to do with the recovery trial and that meeting, which was just 30 minutes. We got the green light to go ahead and get the trial up and running. And we managed to truncate it down just to nine days from getting that green light to enrolling the first patient. We really, over the last decade, have gone from no trials to three and a half months to a month to 20 days and we've had now down to nine days. And as you'll see, that really makes a difference, timing and scale and everything when it comes to epidemic infections. And I'll now hand over to Martin. Thank you very much. And if I have my next slide please. So just building on from Peter's comments about the key principles about quick, big and definitive. I think there are some others that really matter. Clearly we needed robust results and we needed them fast, but we also had to consider the wellbeing of the patients in the trial, many of whom were very sick. Many of whom were essentially alone, but also had to consider the wellbeing of the staff who were going to be overloaded, both in terms of their time pressure and their and the amount of work they were having to get through, but also emotionally. And in those circumstances, really, one has no choice but to focus only on what matters. The conditions and habits of regular clinical trials need really to be left behind. It was really essential to communicate and collaborate and transparency being honest and open about everything that we're doing with the research community, the medical community patients, public, the media, politicians and so on. There's also a key part of what matters. Next slide please. I look back to look forwards and having been a cardiovascular trialist for the last 20-something years and only literally days into thinking about infections at that time. I was reminded about the treatment trials for acute heart attack from the 1980s. Landmark, large, simple trials, studying perhaps one or two drugs. A very simple design, a one-page case report form, focused on outcomes that matter and death, and demonstrating very rapidly that treatments could have modest effects, but really important effects. And those effects could be additive. So if you could find one treatment worked and then two treatments that worked, you'd have incremental changes and improvements on survival. But that ISIS II international study of impart survival trial from the late 1980s, when I was a medical school, on the front page it had a comment, a statement. By far the most important determinant of the success of this trial is the extent to which the responsible physicians and nurses choose to enter their patients. The actual work must be and is absolutely minimal. And it was with that that we set about writing the protocol for recovery. And I quite literally had the ISIS II protocol on the left hand side of my desk. As Peter and I were writing the recovery protocol and working out what were the things that really mattered and how could we focus on those. Next slide please. Well, as I say, simple eligibility criteria, we recognize that we knew relatively little about the disease, but the patients who admitted to hospital were clearly the sickest mortality. Unfortunately for those patients at the time was something like one in four patients would not get out of hospital alive, which is, is, is, you know, clearly a tragedy at a huge scale. We need to focus on that important outcome but also of course the use of ventilators at the time we didn't know simply whether we'd have enough ventilators, or enough staff to operate them. And then also the duration of the hospital stay. Again, we were worried about how many hospital beds and how many nurses we'd have, as we could have didn't have an impact on that it would matter. And then we used randomization. That is, I guess the one magic bullet in the whole of recovery is the coin toss that assigns treatments to patients based on chance and allows fair comparisons. And then again a one page case report form a one page consent form focused on informing patients, rather than simply overloading with with information that is incomprehensible. Focus on a very simple design. Initially, anybody who's admitted to hospital with suspected or confirmed COVID, and then the single coin coin toss, which meant that patients would get one or four active treatments, or no additional treatments on top of usual care, and the outcomes, as I say, focused on mortality next slide please. Over time, the trial became successful as we'll go on to hear about, and that meant that we were able to add in complexity. At least scientific complexity, as we as we proceeded forwards. So instead of a single coin toss patients who go into the trial, for example in January of this year might actually, there might actually be four different coin tosses, perhaps culture scene versus usual care perhaps convalescent plasma, or the monoclonal antibodies versus usual care treatments to prevent clotting versus usual care and treatments targeted at particular parts of the immune pathway for usual care. And as a consequence, some patients a few patients can end up with four active treatments. Some will end up with no active treatments. The other mental principle is we don't know who's going to be best off with doing the trial to find out and find out rapidly. Next slide. Now one of the things about the NHS is that the NHS collects huge amounts of information, all the time on on on patients so I think it's, it's true for all of us certainly in the UK and it must be true. The other parts of the rest of the world to be very difficult to see a doctor or a nurse without them tapping into a computer of some sort, whether it's to check your date of birth, record information like ethnicity or family history, or to record information about what treatments you you're given, and behind the scenes when you discharge from hospital and what and for what reasons and so on and so forth. The information is all there, but even in the so called one HS, it's quite disparately collected is organized on a country by country basis Scotland Wales England and Northern Ireland, and in multiple different data sets. And one of the key aspects of recovery, as we've been able to bring together that data and use that to help us in the analysis. Why is that important? Will it means that we get complete follow up of everybody who goes into the trial if patients move from one hospital or next, because for example that's where the ventilator is, we still know what happens to them. And it also means we don't have to ask questions twice. We don't have to bother the patients by asking them for information that has already been recorded by their own doctors for their routine health care. We don't have to make doctors and nurses are busy enough as it is, record information for a second time, or you can use these routine data systems. Next slide. Now recovery is truly embedded in the NHS. And this slide, which was is a snapshot from October November last year I could have really picked at any time over the course of the last year, but each line each dot represents one hospital one of 178 or so hospitals. And the bars represent the number of patients admitted with COVID to those hospitals during this particular time period. And the dots represent the proportion of all those patients admitted to that particular hospital who are included in the trial. What I can say is that you can see is that some hospitals were busier than others they saw more patients, that's to be expected. Some patients, some hospitals were much more active and able to recruit a higher number of their patients into the trial than others and some of that's to be expected and some of that gives an idea of where there are opportunities for improvements and to learn from the best performing science. After all, roughly speaking about one in 10 patients who are admitted to hospital with COVID over the course of the last year have been enrolled in the recovery trial. Next slide please. COVID can affect anyone so the trials open to everyone regardless of age from less than six months to over 100 years. Sex, I think is around 30 or 40% of female. We have dozens of patients who are pregnant, regardless of ethnicity, 18% of patients of the black Asian and minority ethnic backgrounds, co morbidity, other illnesses, or indeed geography, every single hospital in the country. And as a consequence, recruitment was fast, breathtakingly fast, and you can see in the first wave, if one looks back to that peak on the left hand side is essentially a year ago, then we were seeing around 400 patients entered into the trial each day. Over the January session, when we had our second or third wave, depending on how you count them, we were up to over 500 patients entering into the trial each day. Because we kept it simple, because it was possible to do this, even in the most extreme circumstances in NHS. Next slide please. And consequently, we have been able to study a number of drugs, I think on our 10th, 11th and 12th drugs at the moment, in very, very large numbers. Essentially, for each of these drugs, recovery is the largest trial of that drug in the world of any kind, and yet we've managed to do that all within one trial, all in one country, up until the recent transition to it. The international components and all in one year. Final slide. I mentioned transparency, everything that I've shown everything that we do, we put onto the public website. This doesn't include individual patient data, of course, but it does include all the results, including every protocol, every ethics submission, every piece of training material, how the recruitment is going, so that we're all in this and all in this together, and all trying to solve the same problem together. Thank you. Thanks very much, Martin. It's now my pleasure to introduce Dr Rahal West, who is one of the doctors working at Buckinghamshire Health Care Hospitals, particularly in Aylesbury, who is going to share her experience of what it was like working on recovery at the front line so thank you Rahal. Thank you, Richard. Good morning. Thank you for having me here today. I'm delighted to share my experience of running the recovery trial at my NHS trust. I'm an anesthetist and I work in intensive care at a district general hospital in Buckinghamshire. Next slide please. Throughout the pandemic, especially in the beginning, it has been quite stressful and at times frightening being on the front line. We had to stretch our capacity beyond imagination. When I first looked into recovery trial at the time with so many uncertainties about the best treatment for COVID patient, I thought this trial was crucial. But I also thought this could be a huge undertaking because everywhere you look, it was so busy and we had a small team to start with. It was just me and research nurse. I remember telling her, it's okay. There's no minimum target to recruit. There's no pressure. We can do this. But partly I was convincing myself, but as we progress, the trial was the one thing that I had to hold on to. It brought me hope and positivity during the trying times. Next slide please. After reading the clear and concise protocol and watch a few short training videos, we were good to go. We put posters everywhere, even in the staff toilets to raise awareness. We implemented the trial at our hospital in record times. We found it very straightforward. The amount of paperwork required has been stripped right down to essential. And this made it easier to promote the trial amongst the very busy clinicians. We can do all this as part of our day to day clinical care. And we found that our patients and relatives has been very receptive of the trial. I think the pragmatic nature of the trial is the unique feature when delivering the trial. Next slide please. With the number of COVID cases rising, I realised early on that I needed to build a solid team under a well-informed leadership. So I talked to as many people as I can at the hospital and to make it even easier for our staff, we produce a quick guide as you can see there where staff can just go to refer to. I also felt it was important for me to make everyone in my team feel appreciated while keeping them confident with my support as the lead being present and engaging was vital. So I made myself available 24 hours a day, seven days a week because I feel the staff and clinicians need to feel comfortable with the various arms of the trial and know that the safety of the trial participant is well looked after. To boost morale and competitive streak amongst my recruiting team, I reward them with certificates. We had recruiter of the week and significant contribution certificate because everyone loves certificate and it motivates the team. The work staff has been helpful and very involved and as a thank you, a few boxes of chocolate biscuit at Christmas or out of the blue did go a long way. Find a slide please. On a personal level, I have learnt a lot and I feel privileged to have the experience of delivering this trial. I had the opportunity to do more for my patients. I was able to engage a lot of staff and clinicians about research and I found I was able to involve many trainees and medical students and they had opportunity to learn about research. Which they might not have otherwise and most of them has really enjoyed their experience and so have I. Recovery trial was built into our routine clinical care and I think this is a key that made recovery trial extremely successful and should be the benchmark for future trials. Recovery trial helped me and my patients during the darkest time and for that I'm eternally grateful. Thank you. Thank you very much Rahad. That was great to hear. Thank you to you and your team working so hard in Buckinghamshire and for all the teams in the UK and in hospitals around the world delivering this trial on the ground. So now I'm really delighted to introduce Kimberly Featherston who was on the other end of the trial if you like. So Kimberly developed Covid and she's now going to tell us a bit about her story and how the recovery trial fitted into that. So thank you very much Kimberly. Thank you Richard. So first I was asked could I have my next slide please, my only slide. Thank you. I was asked to tell a little about my experiences Covid before I got to the time of the trial. So throughout having, being a teaching assistant, so being in school even over lockdown and going into school and working with kids. I'd always sort of thought well it's not a case of if I'm going to get Covid. It's more of a matter of when I'm going to get Covid. So even though I'd had that idea in my head when I started to feel, I feel a bit strange. I can't quite taste my coffee properly. I was like no it'll just be something else. I'll do a test just in case. And so when it came back positive I was still in denial a little like it can't be that bad. It'll be fine because at that point I didn't personally know anybody that had had it. So it still seemed like something that's happening somewhere else. But soon as the days went on I got quite short of breath going downstairs and then I would get short of breath walking from one end of the kitchen to the other developing other symptoms and collecting them as I went along. I did go to the hospital to rainy one point on day five I believe it was when I couldn't get my breathing back under control. But my saps were all great so they sent me home with some steroids, oral steroids and anhyl, sorry not antibiotics. A couple of days after that I picked up a bit and I was like okay great I'll turn the corner now it's all going to be great. But then sort of days seven and eight started going downhill again and then day nine I just sat up in bed and felt like my lungs were about this big. I could just take in tiny little hiccups of air and it was quite scary and unpleasant of course. So I still made my partner ring 111 before going to the hospital for some reason and went to A&E and got full of oxygen. I said congratulations you get to stay and all three I was still more or less okay myself so it was a bit strange because I didn't feel the whole fluiness of wanting to just be doing nothing which I kind of expected. So that was day nine when I got admitted and put on oxygen and just started having antibiotics, antivirals and dexamethazone, good old dexamethazone. So I've been in the hospital a couple of days when a doctor came to visit me and the way she said it was a sheepish approach because the way she came up to me was sort of I got the impression she was used to being rejected. She was like oh I'd just like to speak to you about this, you don't have to do it but you know I'll speak to you about it. I said oh is it the trial? I've heard something about the trial because yes it is, it's a little great. Samuel do you want to know more about it? No no it's fine I'll just I'll do it and just keep saying well do you have any questions? Are you worried about anything? No no just I'll do it and it's great I would love to do it. I'm not a scientist but I'm quite scientifically minded, I do teach a bit of science and so I know that trials have to happen so I was really up for it. I was given the visa paper showing in the picture there and I took a picture of it sent it to anybody I thought who might be interested saying this is great. Look what I'm doing, look at the hospitals they're in because for this trial this huge national trials to be happening in you know my little local hospital seemed like a big deal and obviously now I know that every hospital in the country has been involved which is wonderful. So she then came back and told me that I've been assigned to the monoclonal antibodies group which was the ones I wanted so I was happy I don't know why I wanted them I'd have been disappointed if I'd be putting the control group. So yeah I was always really excited to try it and kept every time someone came up to the towards my bed I'd be like oh they come yeah they come yeah it was like Christmas. Finally got them on Monday evening it'd be the Sunday when the doctor came to speak to me so obviously things don't happen that much on Sundays in hospitals and so the antibodies came up I got hooked up to it. I said you know just stay there as you do and and then it went and bizarrely about half an hour after I started having the monoclonal antibodies in my right arm. The left side of my body turned red like I've been sat in the sun my right ear so my left ear was red hot my face was red all this round I don't have any allergies I've never reacted to anything in my life. I didn't feel I was having legit reaction. And I only pointed it out to the doctors because with it being research I thought it was probably something they would want to know. I'm not worried and not bothered just letting you know this has happened and this lovely guy came over and asked me millions of questions kept touching me in various places it was quite personal. And they just couldn't apologize enough and and someone from the research team came over and I was so sorry or give you some of this means was like I'm really sorry this happened. Like no no I'm not worried at all I'm not bothered at all I just thought you probably needed to know for your for your purposes. So there were they couldn't have been nicer they couldn't have been more caring. And it was all over a pleasant experience even if I did have this peculiar reaction to it. Then I thought I'd say something about why I wanted to take part in the trial, because I spent quite a lot of time over the last year feeling like that I should be doing something or I wish I could do something more useful than staying home. At that point staying home as a member of the public is probably the most important thing I could do but I really wanted to do something more. Not that I went out of my way to get COVID to do that but I often felt that I wish I could do more and having a sort of scientific background knowledge. I know that research is the only reason why things happen, why things change and that we wouldn't be here today if we didn't have the benefit of all the medical research that's happened for hundreds of years. I have an inherent trust in science and the NHS I would never for a minute think that they were going to do something that would harm me. So that's another reason I didn't have any concerns and overall just a massive feeling of gratitude for all the work that's been done in the last year and for all the lives that have been saved and people who haven't got sick as they may well have done. And that is my bit and I would just like to say thank you so much to everybody involved because it really is incredible. Thank you. Thank you very much Kimberley that was great. Please, if you have got any questions for Kimberley or any of the other speakers please do put them into the Q&A on zoom or put them into the comment box if you're watching on YouTube. But now I'd like to introduce Natalie Saplan, one of the statisticians who's been working on the trial who's going to give us an overview of the results of the trial today so thank you Natalie. Thanks Richard. Can I have the next slide please. So there's been lots of treatments tested so far in recovery and there's been two successes as you can see in the centre of this slide indicated by the green circle so last summer, relatively early on in the pandemic. It was found that steroids called dexamethazone reduced death in the sickest patients so in patients who are on a ventilator deaths were reduced by about a third. And you also got a fifth reduction in patients who were receiving oxygen but not yet on a ventilator. More recently, in patients with severe COVID, we've announced that toxilisumab also reduces deaths by about 15%. And this is including a people who are already on dexamethazone, which was great news so that means you can combine the two treatments to get even larger benefits so in patients who are on a ventilator you could reduce deaths by nearly a half by giving both of these treatments and reduce deaths by a third in people who are on oxygen but not a ventilator. There have also been some treatments that have been shown not to be effective and these are shown on the left hand side of the screen with the red circles. So for hydroxychloroquine, lipanavir, etonavir, azithromycin and convalescent plasma. There's no evidence that the number of deaths is reduced in participants compared to patients who have been treated with the usual standard of care. And the trial is still ongoing for several other treatments and these you can see on the right hand side of the screen with yellow orange circles. So acultrasine is now closed to recruitment and has it has now been announced that that is not effective and the results for that are being written up. aspirin has closed to recruitment and follow up is ongoing. The results of that are expected around late April, early May. Participants who are currently being recruited into the trial, they could be randomized to three treatments, those being Regeneron's antibody cocktail, varicetinib or dimethrol fumarate. Thanks very much, Natalie. So, in our final talk before we get to the Q&A, I'm delighted to welcome Raf Hamers and Ernie Nelwyn from Indonesia to explain to us a bit about recovery and what it's like taking it internationally. So thanks very much, Raf. Thank you very much Richard for the introduction. It's a great pleasure to speak to you about the experience in Indonesia and taking part in the international branch of recovery. When Peter Horby reached out to us, we were thrilled and excited to be able to contribute to this very important trial and also to be able to include this part of the world in this effort. And at the same time also learn lessons that have let reach beyond the UK and the Western world alone. So I think that was an amazing opportunity for us. So the international branch of recovery is now expanded to include Vietnam, Nepal and Indonesia and is also currently working on including African countries as well. I will be delivering this talk together with Dr Ernie Nelwyn, who is an associate professor at the Faculty of Medicine at the University of Indonesia, and she will be taking over from me after my first remarks. Next slide please. So Indonesia for people who are not so familiar with the country is a big nation in Southeast Asia. It actually has the fourth largest population globally 270 million. The epidemic has hit hard in this country. It has the second highest number of COVID cases and that's in Asia behind India, India, and the epidemic is still ongoing. So it has a huge impact on the health system with hospitals being overburdened for periods of times in different stages of the epidemic. Fortunately, a vaccine rollout has started in January this year. But as you can imagine, there are still huge challenges ahead to reach the large geographically spread population. So the epidemic is definitely not over yet. Next slide. Oxford University has longstanding research partnerships in Asia, but particularly also in Indonesia as part of the Welcome Trust supported Africa Asia program as you can see in the colourful comic cartoon on the right hand side. You can see that the Oxford University has a Centre for Topical Medicine and Global Health and has overseas laboratories connected to that in Africa and Asia and Indonesia as part of that network. In Indonesia we partner with our host institutions and they are premier research institutions in this country's University of Indonesia, particularly their Faculty of Medicine and the Aikman Institute for molecular biology. And we share a vision of striving for excellence in biomedical research of infectious diseases that is important for the country and the region. Most of what we do is clinical trials on malaria tuberculosis and now COVID. Next trial please. Next slide please. So that situation put us in a very good position to connect with our friends and our host and really move very fast in establishing this trial in the country. So it facilitated site selection, the setup and the governance. And so how we work is that the Oxford units in Jakarta provides support to the clinical sites, and we have selected sites, and we created that in a network across the country in major urban cities. And each hospital is then being led by a site principal investigator. I will now hand over to my colleague Annie who will give you some insight on implementation and challenges. Thank you very much. My name is Erine L1, I'm the IED institution in the University of Indonesia, Cilto Mawrgwys Mawr hospital. So for the implementation for recovery trial, we luckily can involve several sites, not only in the capital, Jakarta, but also another sites in different islands. As you can see that we are consists of five big islands. So there's one in Sumatra, one in West Java, East Java, Salafs, and also in Bali. It is well regarding the trial itself at this moment. And there's a support for the for the government. So as you can see here, we can manage to have the approval of ethical committee for only a week. But then since the trial is changing due to the adaptive trial mechanism. So we need everything of course to then do the amendment and it takes some time to do that. But somehow we manage at this moment with two sites, one in the capital and the other one is in Medan. We have already done a trial steering committee. We aim to include 2,000 participants in two years and at this moment for only one month we able to include 80 patient sites. So this is the things that might be different in new case settings because everything is under one control in IHS that makes everything seems easier. But then we have to be able to for Indonesia in particular explain to the authority how they can understand the protocol easily. And then we have to select the site. We have to know who we work with, the team in particular. Also the support and backup and about this I should mention that the backup support from the Aigman hotspot from Dr Raff's teams is extremely needed and important. And we also have to be communicate all the time with the authority to have the easier or smoother process. But still of course we have to be patient with the pills, the drugs, the pharmacy stock because some of it's not available in Indonesia. And then in each hospital you have to sit and discuss about the agreement. And also now since some of the next trial will be using medicine that might be, you know, interpen with the background epidemiology, disease like TB and hepatitis B co-infection. So then we have to also see the local standard of treatment to be safe for all the new trials. Thank you. Thanks very much, Ernie and Raff. That was great. So we're going to go into the Q&A session now. So if you have got any questions, please put them into the box. There is a second poll. If you wouldn't mind, if you go back to the chat on Zoom or follow the link again on YouTube, you'll be able to find another poll which would be interested to see your answers in. But we'll go to Q&A. So if I could ask all of the speakers to put their microphones and cameras on, that would be great. I'll give the first question to Peter if that's all right. Quite a few questions about how did we actually decide which treatments we wanted to test in recovery? What was the, we've tested 10 or 12 treatments, which sounds like a lot, but there are probably hundreds of candidates. How did we narrow it all down? Yeah, I mean, it's 10 or 12 separate trials, which is great, but there's a huge number of potential treatments that have been put forward. And certainly at my inbox, and I know many others has been full with suggestions of things to test. So there's a process that we've gone through looking at various criteria. The first, obviously, is what's the evidence of the likely effectiveness and safety of the drug. We've also then looked at what population group may benefit most from that kind of intervention because there are other trials in prevention, in outpatients who have mild illness or in hospitalised patients like we have or just in intensive care. And then we look at the whether the drugs are suitable for the trial in terms of the number of doses that are available because we're aiming for large definitive results, which requires many thousands of patients to be treated and whether we can deliver the drug within the design of the trial in a way that's safe. And then also whether if we show that the drug works, it's likely to be something that could be scalable internationally. And so currently initially we did that ourselves, but there's now an independent committee that looks at the data called the COVID Therapeutics Advisory Panel, and they review all the data and they make recommendations to us as to whether the drugs come into our trial or into other trials because there are other trials. Now we've not been able to evaluate on all of the drugs, but we're trying to get through as many as we can and those are most promising. Okay, thanks Peter. Raha, could I ask the next question to you, which we've had, which is how did you as a hospital come to hear about the trial? And how do you think we communicate about these trials around the country to make sure that we get all the hospitals in participating as quickly as we can? I think the role of the clinical research network, the clinical research network play a major role in promoting and helping to deliver recovery trial. I certainly hear it from the research department and the CRN about the trial. It's very easy to look into the trial and there's a website that everybody can go into which cater for patients and staff and it's very, very informative. So it's the information's up there, but the role of clinical research network was very important, I think, in delivering and promoting the trial. Okay, thanks very much Raha. We've got lots of questions, so I have to apologise to people if you've asked a question and we don't get to answer it. But we'll get through as many as we can, bearing in mind we need to finish this by 10 o'clock. So the next question for Natalie. Two drugs that work, Dexamethazone and Tosalizumab. Presumably these are now going to be given to most of the future participants. How does that affect the other drugs that we're still testing in the trial? So, well, because we're randomising, as long as, so when these drugs get added to the usual standard of care because we're randomising people between what is their current standard of care and the treatment, it means that we can test whether the treatments in the trial are working on top of what these drugs. It allows us to see whether the drugs work, given the already giving things we know work. Thanks Natalie. Martin, this is a question I expect to be close to your heart. Do you think that the standard practice or common practice say of using drugs outside of a trial out of desperation is justified or should trials really be the standard care essentially? Well, I think there's two sides to that. I mean, clearly there are many parts of the world where there isn't the option of a trial. There simply isn't a trial. Now in the UK we made recovery available everywhere, at least in every hospital. But I do think it is challenging to give to patients a treatment which you just do not know whether it works or not. And you're making a, in a sense, an unjustified and unfounded promise of hope to that patient in the absence of any knowledge about whether you're actually doing them, whether you're actually helping them, harming them or neither. And also remember that these treatments that might be being given on a sort of arbitrary basis. That takes resource, it takes manufacturing, it takes the cost of the drugs, it takes the time of the nurses and the doctors in the hospitals making up those drugs administering those medicines. And remember that that arbitrary process actually means that some patients get these treatments and some don't get them. And actually we never learn about how we should treat the next patient or the next patients as the pandemic and roles. So I really do think that when, as doctors, when there's healthcare professionals, when we don't know what we're doing, and in with a new disease like COVID, of course we don't know what we're doing. That's understandable, that's an honest appraisal of the situation, then randomising is, randomising in large numbers to get a quick and clean answer about which treatments are effective and which ones are not, is the right way to go. And if we look across the course of the last year, patients in the second wave in the UK would, would treat, given better care because of the results we got from the first wave. They were given dexamethazone, they were not given hydroxychloroquine because of the results from the first wave. Patients in the second and third wave here are now being again treated better than they were in earlier waves. And if they were a future wave in the UK, that will also continue to be true. And that is true also internationally. The nature of a pandemic says it in the word is that it's a global problem. And so just as the tide of the pandemic may seem to be going out in one part of the world, it's coming in somewhere else. But the knowledge you gain from one part of the world becomes incredibly important in other parts of the world. So I think it is absolutely the case that when we don't know what we're doing, and we don't, and there are good reasons for that. And there's lots of reasons for believing particular drugs are very likely to work or very unlikely to work. We have to do randomisation. If I look back on the results of recovery, I think for every drug that we have got of results, it has gone against a large wave of popular and apparently well informed medical opinion. We've had people tell us we shouldn't randomise patients dexamethazone because suppressing the immune system would be dangerous. We've had comments you should, you must be giving everybody hydroxychloroquine because it obviously works. Those are well, many of them are well reasoned, well argued positions. But the bottom line is, if we don't know what we're doing, then we better find out and we better find out fast and the randomised trials are the way to do that. You can't do that unless one, there's a randomised trial. And secondly, that it's actually practical. There's no good saying to a frontline doctor like Raha. You can't prescribe anything. You've got to do this trial. But by the way, this trial is going to take you hours and hours per patient in order to do it. You've got to be in feasible. You've got to, you've got to strip this down to the things that really matter. And that's a way we improve the outcomes for patients wherever they are in the world affected by COVID. And indeed the same rationale applies to many other conditions. Thanks, Martin. Kimberly, there's a question for you if that's all right. Members of the audience would like to know how you're feeling now. And I'd like to know if you ever look back on what you did in recovery and had it ever had second thoughts. Certainly never had second thoughts. How I feel now. I've got long COVID, which is great. And I do still have some issues. But I don't think that's related in any way to recovery. The majority of people who go on to develop long COVID never actually were hospitalized. I don't know if this implication that that might have been being related. But yeah, I'm still having issues, but I'm certainly a million miles better than I was when I was acutely unwell with COVID. Great. Very pleased to hear it. Okay, we're just coming to the end. So if you've got a question that you're very keen to ask, please do get it into the chat as quickly as you can. RAF, maybe a question for you. Do you think that trials like recovery could change the way that we do trials in the future? Maybe specifically in Indonesia. Do you think the simple procedures could set a new template for how other trials could run? Well, I think it's a great question. And I truly hope so because I think what you see in our setting is that trials like this are often slowed down by bureaucracy. People, many committees, many authorities needing to take decisions which slows down the process. And I think what we are now showing that we can do this trial within current regulations, but pushing the limit and being closely engaging with the authorities that this is also a way of doing a trial. Very simple, very dynamic, like an adaptive design. I think that is also pretty new to our ethics committee and regulatory authority. I think in doing so, I think we can also build capacity in those committees so that they in the future can also accommodate those types of trials. So I think it actually is very helpful for taking on these trials in this setting. It's a very great experience for everybody involved. Thanks very much, RAF. We're very near the end of time now, so I'm just going to ask maybe to Peter and Martin. There's a question in the Q&A. Whoever wants to answer first can take the easy one, the other person will be left with the hard one. What do you want to do the same again next time? And what would you do differently? I'll start because I'll give a slightly different answer to Martin. I know, I mean, I think the issue for me is how can we export the design? Most of the threatening infections may occur in lower income settings where we don't have the infrastructure. For me, I really want to learn is what elements of this can we take and export so that we can use it in diseases like Lassa fever in West Africa or virus in Bangladesh in places like that where we will struggle with some of the issues that would be much easier within the NHS. I don't think I would have done much differently to be honest. I mean, I think there's little tweaks we can do to improve how things were done in the UK. And I think the big lesson is that we should keep these platforms open because we have ongoing respiratory infections like respiratory sensitivity to a virus influenza. We should keep these platforms open and try and improve care for those common common garden diseases. And then we'll also have the platform ready for if anything like this unexpectedly hits us again. Martin. Well, I think given how little we knew at the time and the speed at which we set up. In a sense, good fortune was on our side. I think we, there's not a whole load that I would change about the way that we did this particular trial in the UK. I would say that I would have moved to the sort of factorial design much earlier on. In fact, I might even have started there because that allows us to study multiple treatments simultaneously, as well as the interactions between those treatments. But I'm with Peter. I think that the question is how does what going forward is how does one use this sort of platform. One thing is that the virus moves around the planet pretty, pretty fast, moving a trial around the planet moves remarkably slowly by comparison. And I think we have to internationally we have to fix that so that the trial can move as rapidly as the virus does. But, you know, I said earlier on my own area is largely in cardiovascular chronic diseases are not in the research infections that Peter's talked about. And there's so much about this platform that we could use to understand even quite simple questions in the treatment and management of heart disease diabetes obesity osteoporosis chronic lung diseases mental health and many other areas. But getting randomisation of randomized trials as part of her routine part of clinical care is the way in which we can drive improvements in so many other conditions. I think that's the way forwards. Okay. Thank you very much everybody. We've just put a slide up now there's a huge number of people to thank for an event like today. First of all, I'd like to thank all of our speakers for all of their time and their excellent talks. And so, for a trial that there's, there's too many people to thank but we have to thank the people who funded all the agencies that supported us. I'd like to give a special thanks to members of the team in Oxford, who really worked tirelessly over the last year to deliver this to all of the sites, right high and all her colleagues around the UK and around the world you've delivered this trial. The biggest thanks has to be to all of our really brave participants who, like Kimberlade of terrifying time in their lives were brave enough to say yes to that invitation and contribute such invaluable information so our biggest thanks really goes to them. Just as we wrap up there is a poll, another poll if you're willing to just give us your opinion. And this time as an opportunity just to give three words up to three words that you associate with the recovery trial so the link is in the usual place. And this webinar has been recorded and will be available at the address that you can see on the screen that will also be in the chat and zoom and on YouTube. We'll be able to be viewed in the future should you wish to watch it again or get any of your friends, families or colleagues to watch it, but thank you very much indeed for your time this morning. I hope you enjoyed it. I hope you found it educational. And thank you very much. Goodbye.