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COVID-19 clinical trials. Remdesivir, interferon. How to understand? (3)
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Professor Evans, there are more than 1500 COVID-19 related clinical trials registered at clinicaltrials.gov website. What clinical trials on COVID-19 treatments do you consider most promising today? Well, the trials that have reported so far have not really given in any situations, really full results. There were a number of trials of the treatment remdesivir there. And the first two of these trials were done in China. And both of them ended up stopping because the number of patients that they could recruit who had been admitted to hospital with COVID-19 symptoms had fallen such that they couldn’t recruit. The epidemic was moving on. One of those trials has reported and is reported in The Lancet. Another much larger trial sponsored by the NIH but not just done in America done in Europe and elsewhere in the world. Also compared remdesivir with a placebo. And it has not yet certainly on this date, as far as I’m aware, the 20th of may reported its results other than in a press release from the NIH. But the data that have been supplied to the FDA have allowed them to grant remdesivir an emergency use authorization. The company making the drug has not done any personal Bow control trials itself, as far as I can tell, and there are none registered with the company as a sponsor, but they have compared two different treatment regimes of five days and 10 days treatment with the drugs and have done quite large numbers of those. But those trials do not show you whether remdesivir actually does any better than nothing. It just shows you whether there is a difference between five days and 10 days treatment. And you can count the number of people who have serious adverse effects and make a historical comparison or a comparison in your mind to say whether it is seen to be safe. And the data from those trials combined with the data from the placebo controlled trials, obviously was enough for the FDA to grant emergency use authorization They did not give it a license for marketing, saying that the evidence was sufficiently convincing to make the company allowed to sell it as being effective in COVID-19. And they found differences that we’re in the time to recovery. The differences in mortality between those treated and those untreated, was only marginal. And the Chinese trial was one that we would call underpowered did not recruit enough people to show whether there was a real difference either in time to recovery or in mortality. The results were simply too uncertain. And so it’s not right to say that the trial in China and the trial from NIH were contradictory in the fact that the NIH trial found evidence of benefit in recovery time and the Chinese trial didn’t. It’s just that the Chinese trial was too small to detect a difference. But it also didn’t find any difference in mortality. Whereas the NIH trial found a slight difference in mortality that, if it were real, would be of benefit. But again, it was in the press release, at least, underpowered to determine whether there was a genuine benefit in mortality. The other thing in these drugs with remdesivir there in particular, but also a number of other drugs, is that they are intended to attack the virus directly, rather than attacking the symptoms that the virus causes. And so some drugs are targeted at the virus, and some are targeted. symptoms, but for the antiviral drugs like render severe, they’re targeted at the virus. And the consequence is that if you give the treatment too late in time, the virus has multiplied so much in a patient that it’s too late to prevent the symptoms. And so for a number of treatments that are intended to knock the virus sale, you have to give it early on in the course of the disease. And so, sometimes the results have been split up to produce subgroups that divide people into those who got the treatment early, and those who got it late. And, as you might expect, those who get the treatment early after symptoms have occurred. If the drug is effective against the virus, it will do better than that. Those who got the treatment later. Now, of course, you can’t randomize people to get treatment early or late, you’re going to just have to accept that. So these subgroup analyses are not any longer based on a random comparison. So they have to be treated with a great deal of caution. But in this instance, it is entirely reasonable to think that giving treatment early will have bigger benefits than giving it later. The problem slightly with this is that we know now that the virus is probably at its maximum just prior to symptoms appearing or just around the time of symptoms appearing. And infections, as it happens, is also at a maximum then, which is partly why the virus has spread around the world. So we weigh the consequences that you may have to give treatment. And ideally, you will give the treatment to people before they had any symptoms. And then you might be able to stop the virus replicating and stop them from getting symptoms. But you want to give it very early. But of course, people don’t go to the hospital until they’ve had symptoms for a little while. And so this is a difficult situation if we were able to test people early, or we had really good diagnostic indicators of early onset of COVID-19, then we could do trials in there. And so for example, if we could do trials in everybody who got a sudden onset of taste and smell, and who may have COVID-19, we might find that these drugs were really very effective, and we wouldn’t necessarily have to treat large numbers. The same kind of thing. the pattern has been seen in a trial of interferon that was run in Hong Kong. injectable interferon was given there together with two drugs that were given in HIV. And in the Hong Kong culture, you can’t really easily run a trial with placebo. So, both groups got the two anti-HIV drugs, while the group with remdesivir there with interferon, sorry, with interferon, the two groups with interferon, the group with interferon had interferon plus the HIV drugs, and it was compared with the HIV drugs alone. But again, this study was quite small. It showed real benefit in recovery time, but it didn’t show sufficient benefit in mortality. For it to be statistically significant, but this was intended as a small trial and was intended to move on to another trial. In the UK, there is another trial of interferon beta but not being given by injection, because that drug is given by injection to patients with multiple sclerosis. But it’s a trial of interferon beta given directly into the lungs by inhalation, but we haven’t got the trial results from that. But both remdesivir there and interferon beta are the two treatments for which we have some evidence of their being successful. For hydroxychloroquine. So far, we have no evidence for azithromycin so far, and we have no evidence for the combination of them. We have no evidence and, in fact, for the two anti-HIV drugs against So far, we do not have evidence that they are effective in randomized trials in COVID-19. They may be undoubtedly are effective in HIV, but they aren’t effective in COVID-19. So there will probably be some other treatments that are more effective. There are other antiviral treatments, but we have not seen results on these yet. And the repurpose drugs. Interferon is possibly the only one for which we have convincing evidence. There could be other treatments that are important at other stages of the disease. It could be that certain forms of anticoagulation are valuable at a late stage of the disease after the virus has produced the damage. It’s leading perhaps to coagulation disorders, and so having some form of an anticoagulant may help, but again we have no randomized trial evidence suggesting that that is so.
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