Welcome to another MedCram COVID-19 update, and while daily new cases in the United States as a
whole seem to be on the rise, the daily new deaths in the United States seem to be flat at least for
now. One of the things that we've attributed this to, among many other things, is the new therapeutics
available to us in the hospital to use on these patients that are admitted with COVID-19.
And indeed for months now, one of these medications that we've been using
in the hospital is remdesivir, and about a week ago, there was the final report
on "Remdesivir for treatment of COVID-19" article published in the New England Journal of Medicine.
And in the article it says that a total of 1,062 patients underwent randomization
and one of the endpoints was the time to recovery, and this article showed that in this study, the
time to recovery was reduced from 15 days down to 10 days, and this was statistically significant.
Now in terms of mortality, after just 15 days the mortality rate in the intervention, or remdesivir
group, was 6.7, and it was 11.9 in the placebo group, whereas by day 29, the mortality rate with remdesivir
was 11.4 percent, and with placebo was 15.2 percent. But as you can see, the confidence interval
went from 0.52 to 1.03, and what this essentially means is because that range includes the number
1.0, they can't be sure that there actually was a statistically significant reduction in mortality.
In other words, we can't say with 95 percent confidence that there's any difference between these two
groups. Now, that's an important distinction, because before, remember, they had stopped the study early
to see whether or not there was an end point that was made, and this is what gave remdesivir
the emergency-use authorization. It was that it reduced the time to recovery from 15 days to 11
days, initially, and this final report is showing that it reduced it actually down to 10 days,
but, as we can still see, no reduction in mortality. Now what I find interesting is that when they
looked at serious adverse events, there was 24.6 percent adverse events in the remdesivir arm -- in
the intervention arm, in other words -- and there were more adverse events, 31.6 percent, in the placebo
arm, which is counterintuitive; normally you would expect to see more adverse events coming from
the medication that's active. We always typically would expect that, because there is always a risk
and a benefit to any kind of intervention. We're hoping, however, that the benefit outweighs the risk,
and here you can see something called the Kaplan-Meier curves, and of course we'll publish the link
in the description below to this New England Journal of Medicine study, but you can see here
the proportion that recovered, essentially a survival type of Kaplan-Meier curve, you can
see here that for all comers, overall remdesivir had a higher line than placebo, but apparently not
statistically significant. Now these lines become a little bit more blurred and closer together when
we look at patients receiving high flow oxygen or even non-invasive mechanical ventilation, which is
one of those masks that we can put on patients and do BiPAP or CPAP, et cetera. Now when we look down here
at patients receiving ECMO or ventilation when they're actually on the ventilator,
these two lines essentially are overlapping, which would mean that the longer you wait or
the more severe these patients became, the less of a magnitude we saw an effect from remdesivir. The
other interesting aspect of this is when you look at the demographic and clinical characteristics of
the patients at baseline. Here, we see in the first column, all of them, over a thousand patients, and
here we see the remdesivir and placebo group, and what you typically would like to see is that there
is an equal number, generally speaking, in both. It doesn't really state here whether or not any of
these were statistically significant, but there is a couple of things worth pointing out here.
First of all, when we look at coexisting conditions in these patients, they're generally similar with
remdesivir actually having slightly more type 2 diabetics and slightly more patients with obesity,
so that would tend to put remdesivir at a disadvantage in terms of how this study was
to come out. However, when you look at the score on ordinal scale with some of these patients who are
hospitalized, when we look at the most mild patients who are in the hospital number four, here
we can see that there was more patients who were mild in the hospital under the remdesivir group,
and when we look at hospitalized patients requiring supplemental oxygen we did see
more of those patients here in the remdesivir group than in the placebo group. But when we start
looking at the more severe patients, the patients that you might encounter having complications or
adverse events -- for instance, hospitalized, receiving non-invasive ventilation, or high flow devices -- what
we start to see is that there is a swing where the placebo group seems to have more of these patients,
and that is seen most in this last category, where we have hospitalized, receiving invasive mechanical
ventilation, which are the worst patients or even ECMO. And clearly here you can see that in the remdesivir
group, there was 131 of those patients (or 24.2 percent), whereas in the placebo arm there were
154 patients (or 29.6 percent of those patients), and it would seem as though that would put the placebo
arm at a distinct disadvantage, if in fact that was statistically or even clinically significant.
Now, I'm not a statistician or epidemiologist, but that would just be in my humble opinion,
and one could reasonably say that if that was statistically and clinically significant enough
it's possible to see how it might give the remdesivir arm a look of an advantage, potentially.
I don't know if that's the case in this particular example. Now, why would I bring up something like
that? Well, because just today as we are recording this on October 15, there is some breaking news
about remdesivir and the solidarity trial coming out of the WHO, so if you're not familiar with the
World Health Organization's Solidarity Trial, let me introduce you to the concept. Their "rationale" as
it says here on the website, was to have a single randomized trial that would help look at the most
favorable and promising interventions with a control group to see whether or not it would
overcome the risk of multiple small trials, not generating the strong evidence needed to determine
the relative effectiveness of potential treatments. Wo what were the treatments that were looked at?
So we will turn to this Reuters story, "Remdesivir did not reduce mortality in COVID patients."
This WHO's Solidarity Trial looked at four potential drug regimens, including remdesivir,
hydroxychloroquine, and the combination of lopinavir and ritonavir, and finally
interferon, and they looked at this in over 11,000 hospitalized patients,
which would be the largest trial to date looking at these medications. Now the WHO stopped
recruiting to two of these trial arms, specifically the hydroxychloroquine and the lopinavir/ritonavir
in patients that were hospitalized back in June, after they say they proved ineffective. However,
the other two arms were looked at more detail, at 500 hospitals and in 30 different countries,
but what we can report tonight is that this study that was completed found that none of those four
treatments substantially affected mortality or reduced the need to ventilate patients.
So let's go and take a look at the preprint, which is available at Medical Archive.
You can see here it was released on October 15, and here you can see all the different agencies
and steering committees for this WHO trial and the methods were quite simple; it says here that
study drugs were remdesivir, hydroxychloroquine lopinavir fixed dose combination with ritonavir
and interferon beta-1a that was mainly subcutaneous, because it doesn't matter whether it was given
subcutaneous or intravenously. They say here that COVID-19 inpatients were randomized
equally, between whichever study drugs were locally available and open control. The intention to treat
primary analysis are in hospital mortality, in the four pairwise comparisons of each study drug
and its controls. So it's important to be number one prospective and number two have a control,
so you can see whether or not these work. So to give you an understanding about how many of
these patients were allocated, you can see here that 2,750 patients were allocated remdesivir,
954 hydroxychloroquine, 1,411 received lopinavir, 651 was interferon plus lopinavir, and 1,412 only
were given interferon, and that there was a full 4,000+ that received no study drug. And there was
good compliance with 94 to 96 percent. When we look at the results we're going to have the drug listed
here, remdesivir, and then we're going to have something called an RR, which is the relative risk,
and then it's going to tell us a number. If that number is less than one, then that would
mean that there was a numerical trend to the drug being good for the patient, as opposed to a number
that's higher than 1.0, which would show that the drug would be tending to be less good or more risk.
There's more to it than just that; you've got to look at the confidence interval,
and if the confidence interval shows that it includes numbers on one side of one or the other
side of one, then you can say with confidence that it is statistically significant. However
if the confidence interval includes the number 1.0, then there is no certainty that this is
statistically significant. And in addition to that, the authors here have also put the p-values in.
If the p-values are less than 0.05, then that also shows significance. So you can see here, clearly,
that remdesivir, while it does have a RR that is less than 1.0, unfortunately the range includes 1.0,
so it's not statistically significant, and we don't have a statistically significant p-value.
Same sort of thing with hydroxychloroquine, although this time the relative risk is greater
than 1.0, but as you can see here it includes the number 1.0, so it is not statistically significant.
And that's again confirmed with the p-value being not less than 0.05. The same goes for lopinavir
and also interferon. None of these have a RR that is less than 1.0, and also a confidence interval
that does not include 1.0, or a p-value that is less than 0.05. And of course, they mention that
here, saying no study drug reduced mortality. Here, we can see again the Kaplan-Meier graphs. Here is
the full graph, and if we zoom in on the particular range that this is over, in terms of mortality,
we can see that with remdesivir versus control, there really isn't much difference
whatsoever. Here we see hydroxychloroquine and its Kaplan-Meier curve. Here we see lopinavir and its
control; we see that lopinavir actually is a little bit lower on this one, but did not meet statistical
significance. And here we see that interferon looked as though it was actually higher. In fact
in any of these subgroup analysis for any of these four medications that were used, there wasn't a
single subgroup in any single intervention arm that showed statistical significance in terms
of mortality. Now the one thing I would mention is that again these are all patients that were sick
enough to be admitted to the hospital. Now in this, they did look at some studies that have been done
previously, and again, there was some things they showed that were statistically significant and.
particularly, here in the A-C-T-T trial, or the ACTT trial, that looked at remdesivir
in the low flow oxygen. Notice here that the confidence interval goes from 0.11 to 0.81
and here for the first time we see a confidence interval that does not include 1, and it's clearly
on the left side of this line, and this is looking at mortality. It seems as though in a subgroup
analysis of this particular trial, there was an improvement in mortality there. And we see here
in subtotals for lower risk groups patients for instance who are not on the ventilator
almost meeting statistical significance where it is 0.63 to 1.01, so just going over the line
and therefore not meeting statistical significance, but very very close, whereas clearly in higher risk
groups, we have the opposite effect here, but still cannot say that it is statistically significant,
because it does include 1.0. So, basically, big news. I invite all of you to look over this paper that
has not yet been peer reviewed, and tell us what you think. It's quite interesting that just a week
ago we have a positive paper that is published in the New England Journal of Medicine on remdesivir
and then we have another article here that is pre-printed and not yet published showing that
basically no difference in terms of mortality for remdesivir and three other interventions
in a very, very large study. Take a look, tell us what you think. Thanks for joining us!
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