well welcome to this video now i've had
so many requests
to look again at hydroxychloroquine and
that's exactly what i've done
and i've found a study from belgium that
gives
fairly strong evidence in fact i would
say quite strong evidence
that low-dose hydroxychloroquine is
an effective treatment it is an
effective treatment
and it seems to lower the death rate by
about 30 percent
quite profound difference and the
key seems to be that they used a much
lower dose than the other
studies now i am going to
tell you briefly about three other
studies as well that showed efficacy
that showed hydroxychloroquine does seem
to be an effective treatment
but then we'll think about why studies
have shown that it's not and we'll talk
about the recovery
trial from the center of oxford-based
medicine which showed no effect
and discontinued it from the trial and
we'll talk about the world health
organization solidarity solidarity
trial which did much the same thing
discontinued from the trial
and then as time permits we'll have a
look at a study from brazil as well
which shows no effect
but it seems the key factor that people
have been getting wrong i'm just coming
to the end of the bottom line now
just stick with me if you want the
bottom line the key factor
seems to be that these studies gave too
high a dose
now let's clarify what we're talking
about here we're talking about the world
health organization and we're talking
about the oxford center for
evidence-based medicine
they didn't seem to realize you had to
give the right dose
now this is bemusing at best
now is hydroxychloric on a new drug no
we've been using hydroxychloric in its
predecessor chloroquine
for decades absolutely decades for many
conditions so it's not a new drug this
is a drug that's known
the side effects are known the doses are
well known
and yet the world health organization
the center of the center for
evidence-based medicine oxford seem to
get it wrong what is going on here
this is bemusing you know there's quite
a few things in this pandemic and you
just can't work out why people didn't
seem to realize things or get things so
wrong
let me just give you evidence for that
before i finish the bottom line before i
go into the detail
for those of you uh who don't have
enough time for this video
now this i've just taken this this
morning from the british national
formulary
now this is what all doctors and nurse
prescribers and pharmacists in the uk
use it's absolutely standard
hydroxychloroquine sulfate indications
and dose
right so d-o-s-e dose there's nothing
hidden here this is just obvious stuff
and if we look at it we see that the
normal dose is two
to four hundred milligrams daily daily
maximum dose to be based on ideal body
weight
okay so there's the dose for most adults
two to four hundred milligrams
this is absolutely standard public
domain information
and yet both of the studies that we're
going to look at the uh
the uk study in the world health
organizations that didn't seem to
realize this so
it's all very strange anyway so that's
the bottom line if you want to skip this
video
fine that's that's good um if you want
the detail i'm going to give you the
detail on the study from belgium that
shows efficacy
first of all then a few other brief
studies that show efficacy as well and
then i'll show you
why it seems these other studies got it
wrong
now let's start off with this study from
um
belgium now i know i'm on pretty thin
ice here so
i know it's been a controversial topic
and to be fair i've probably stayed away
from it more than i should have done
but everything i'm going to tell you
today is based on my understanding
of the science
my understanding of the science and i'm
going to give you the the references for
everything i'm going to say
so this is not opinion this this is this
is my attempt to explain to you what
these scientific papers are about
and and the bottom line i get well i
know i've given you the bottom line
but the bottom line is i'm convinced by
this belgium study
the data is of of as far as i can see a
very
high caliber because they gave a lower
dose
uh now um let's go on to it
so this is the study from uh belgium
low-dose hydroxychloric in therapy right
so so that's the study there
now let's let's notice it's an
observational study so that's not ideal
as we know we like
randomized double blind control trials
when we can
but an observational study of 8075
patients
is a significantly large
study this is potentially good stuff and
it's fully published it was published on
the 24th of august international journal
journal
of antimicrobial agents now the
background that this study gave and let
me just give you a bit of a bit more
background first of all
um the the most of the data here in this
dutch study
i know it's only just been published
most of the data was collected in april
may
at the peak of the the belgium epidemic
there was huge numbers of cases in
belgium large numbers of fatalities in
fact belgium
i think i'm right in saying had the
highest
death rate per capita in europe at least
at least for a period of time it was
very severely affected
so they had plenty of opportunity to do
this study and they followed
early world health organization thinking
that
hydroxychloroquine could be efficacious
so what they belgium authorities did
they included in national guidelines
so you had doctors all over belgium
reading these guidelines and prescribing
low dose accordingly that's where all
this data
came from so over 8 000
patients so the background to this study
is hydroxychloroquine has been
used largely used and investigated as a
therapy for covered
19 at a total dose usually ranging from
2
400 milligrams to 9 600 milligrams
now these are very this is a very large
dose because remember
the dose that's available there for the
world to see
is two to four hundred milligrams
no secret public domain you know
whenever you're
writing up a drug at work i i don't
normally prescribe
but but whenever people are prescribed
are writing up drugs
or i i i look up these drugs frequently
myself but
um you always look up in the british
national formula
the nice guidelines in the british
national formulary it is definitive
if you don't go by those guidelines you
will be negligent
you will be professionally negligent
this is what we go by all the time
and the guidance there was clear let's
look at it well no we've looked at it
enough times
look at it one more time just to be sure
i mean it is what it's saying it's two
to four hundred milligrams um
you know it it's there it's publicly
available no and and yet
let me just give you i've just sketched
out some of the studies that we're going
to be looking at
now um the dutch study
used 400 then 400 milligrams on day one
and then 200 and 200 milligrams on day
two to five so in other words 200
milligrams twice a day after that first
dose
so that's what the dutch study was
giving now the recovery study in the uk
was giving 800 milligrams followed by
800 milligrams after six
hours you know absolutely incredible
let's just remind ourselves of the the
the appropriate dose in the british
national formula
two to four hundred milligrams
why were they giving such a high dose
i i am bemused so they gave 800
milligrams
stamped they gave 800 milligrams six
hours later then another 800 milligrams
12 hours after they gave that first dose
then they gave 400 milligrams twice a
day
400 milligrams twice a day from days two
to nine
whacking great dose
and um yeah we'll leave it at that for
now
so we can see the difference in those in
those studies and the world health
organization trial likewise was giving
much much
larger doses compared to the dutch study
that was giving
way lower doses so days two to five
the dutch study was consistent with the
guidelines we've known about for decades
that they seemed to be aware of that
whereas the other studies didn't seem to
be able to work out
i don't know i i can't quite i'm trying
as you see i'm struggling to work this
out
um i hadn't the impact of this hadn't
hit me till until i
prepared for this video actually but in
belgium off-label use that means it's
not officially used for that purpose but
it was
uh of low low dose hydroxychloroquine
and and they gave us total of
400 milligrams over the five days
2 000 so that's 2.4 grams isn't it
over the five days 2
400 milligrams over five days low dose
regime so 500 milligrams twice on day
one 200 milligrams twice on day two to
five
a total of two thousand four hundred
milligrams
so that was what they were giving in the
uh in the dutch study
right now the method that the dutch
study used
uh multi-center design which is good
um vast majority of belgium hospitals
are included
it's always good when you get different
geographical areas it was a
retrospective analysis now to be fair a
prospective clinical trial would have
been better
but this is based on a lot of numbers so
it's quite convincing
uh they looked at inhospital mortality
in belgium
and that was one of the outcomes how
many people died in hospital
but as well as that they looked at the
outcomes after um
after 40 days and they were able to put
patients in groups
so there was no difference in the
baseline characteristics
in other words they weren't putting
people with lots of comorbidities
in one group because obviously if lots
of people had high blood pressure in one
group and
lots of people had normal blood pressure
and another group that would mess things
up but they didn't they accounted for
that
and they accounted for that using this
tool here
which is the recognized comorbidities
now this is the hazard ratio so 1.5 that
means an event will be 50
more likely that means it would be twice
as likely that means it'd be two and a
half times more likely
so as we can see all of these things
here make death and adverse outcomes
more likely
male sex makes it more likely every 10
years of increasing age
makes death and adverse events more
likely
chronic liver disease there we see makes
it more likely
so they took into account all of these
well recognized
comorbidity risk factors
so this is quite a clever study and if
you actually look at the people that
were doing this it's all clever
mathematicians and epidemiologists and
doctors from from all over
all over all over belgium so it's quite
a sophisticated
piece of work actually so they could
took into all those things into account
so no difference in baseline
characteristics in other words they
weren't comparing apples and oranges
they tried to put people of the same
characteristics in
in the groups now in the groups they
came up with
they were first of all there was
hydroxychloroquine
alone with supportive care when i said
low they didn't mean they didn't give it
with anything else it was just
hydroxychloroquine
and all the usual care that the patients
got of course all the usual care as well
as
so the hydroxychloroquine was as well as
the usual care
and then the second group so that's the
first group and if you like the control
group
that they just got supportive care only
they didn't get the hydroxychloroquine
so they get everything else they needed
if they needed oxygen they get oxygen
they needed antibiotics to get
antibiotics they just didn't have
hydroxychloroquine that was the only
difference
between the between the groups
so um so that's good uh the adjusted for
demographics as we said
they adjusted for all those things the
results
8075 patients with complete
discharge data wow that's impressive
record keeping there from the belgian
authorities now the hydroxychloroquine
group
uh there was four thousand four and a
half thousand patients in that good
number very good number in fact
and in that group uh 17 died
during the hospital stay
in the group where there was no
hydroxychloroquine
27 died during the hospital stay and for
these numbers that is a very
significant result the results of that
arising by chance are
minuscule it's a very significant result
so they were the deaths in hospital
and uh they did so they did a
multi-variable analysis as i said
looking at all these different factors
you know the obesity the high blood
pressure the heart disease they
accounted for all that
and they still found mortality was low
in the hydroxychloroquine group group
compared to the none
hydroxy chloroquine group and the hazard
ratio was
uh 0.684
so in other words if you had 100
patients
surviving uh in the uh none
in the uh in the hydroxychloroquine
group
you would only have uh 68.4 surviving in
the other group
so it's reducing the chances of
mortality
quite significantly if it was one it
would be the same if it was 1.5
you'd have a 50 percent greater chance
of dying so we see
there's actually about what is a 68 so
there's over a 30
reduction there which is impressive a
hazard ratio of 0.684
an impressive result i feel and also
they did
follow-ups uh for 40 days 40 days
and after 40 days the group that had
received hydroxychloroquine alone
uh 19.1 percent of those had died
whereas in the group that did not get
the hydroxychloroquine 26.5 percent
had died pretty convincing mortality in
the hydroxychloroquine group was reduced
uh both in patients diagnosed in less
than five days and more than five days
so even if the treatment was started
latish after five days
they still had a significantly reduced
mortality right
that's what the study found in belgium
that is
quite convincing now the conclusion of
the authors
they came to this conclusion
uh compared to supportive therapy only
low-dose hydroxychloroquine monotherapy
that's just that on its own
with no other uh suspected antiviral
agents was independently associated with
lower mortality
let me put that another way it means
less people died in hospital
with covered 19 diagnosed and treated
early or even it was treated later on
in the symptomatic phase so
that is good evidence
to me that low dose hydroxychloroquine
let me rephrase that correct dose
hydroxychloroquine
why am i saying correct dose
hydrohydroxychloroquine
because we go by the british national
formulary that tells us
what the correct dose is
so really quite uh
impressive results and really quite
bemusing why the centers for
oxford-based medicine and why the world
health organization
seemed to use such a large dose
and of course the other great thing
about hydroxychloroquine it's generic
you can buy it for nothing it's
peanuts i don't know how much it cost
but i imagine you can buy a thousand
doses of it for
you know a few dollars literally
literally three or four dollars
for a thousand doses is the kind of
price that i use i used to buy a lot of
generic drugs
um when we used to export them to
romania in the early 90s
and that's the kind of price we were
paying typically a few dollars per
thousand doses for these generic
off-license drugs basically it's just a
chemical and it's
it's dirt cheap and we
obtainable in huge amounts at very high
quality
as well with guaranteed quality not a
problem
um now other positive studies
i'm not going to do these in detail but
um there was this one here for
example in france so that study
that's the reference don't take my word
for it
and the conclusion of that study was
early diagnosis early isolation and
early treatment have covered 19 patients
with at least three days
of hydroxychloroquine and they gave
azorthyprin as well
led to significantly better clinical
outcomes and a faster
viral load reduction than other
treatments so they found efficacy
of that combined therapy
it's not as a thyroid so it's another
one i can't remember i'll we'll come on
to it later on it's an antibiotic
um risk factors for mortality in
patients with covenant 19 and new york
study
hydroxychloroquine was associated with
decreased in hospital mortality
and when i put it in italics these are
direct quotes from the
paper and again don't take my word for
it it's there look it up
click on that in the in the description
that goes straight to it
um and again treatment for
hydroxychloroquine
uh that that is that's a azithromycin
it's an antibiotic that's the word i was
trying to remember
azithromycin uh azithromycin has been
used sometimes because it's got
um anti uh
in vitro and the bench it's got
anti-viral properties
and it's got um immunomodulating
properties as well that's why it's
sometimes been used
but of course remember the dutch study
was not using erythromycin it was just
using hydroxychloroquine as a
monotherapy
and of course the reason
hydroxychloroquine is used is because
it's got these uh
in vitro uh antiviral uh effects
as well um so the theory the theory for
hydroxychloroquine and the theory for uh
azithromycin
are both good the theory is there
um treatment to load with
hydroxychloroquine and in combination
with
erythromycin was associated with reduced
mortality so that was saying giving the
hydroxychloroquine alone as a
monotherapy or
giving it in combination with the
azithromycin with both associated
with reduced mortality
so quite a few studies there on the
efficacy of
low-dose hydroxychloroquine
now how did we get to this state where
hydroxide has been virtually
dismissed well the recovery trial
was was won and at the time this looked
pretty convincing because this is from
the center for over x this is from the
oxford center for
evidence-based medicine this is not some
mickey mouse organization
but as we looked at
they were giving on this trial 800
milligrams 800 milligrams 800 milligram
for um 400 milligrams so
um on this trial we're giving what 16 17
18 19 20 they were giving
2 000 milligrams in the first 12 hours
let me say that again on the recovery
trial they were giving 2 000 milligrams
in the first 12 hours
recommended dose is a maximum of two to
four hundred milligrams
yeah so um
[Applause]
just briefly the this trial we did look
at this in detail at the time
now the numbers look good and then
indeed the numbers are good the
hydroxychloroquine group got uh
that many people the uh control group
got well over three thousand so good
numbers
look it up here it's all still there
it's all documented
patients allocated the hydroxychloric
and sulfate group
you got that fairly high dose and that
came out to 9200 milligrams over 10 days
so much larger dose
than the belgium study
much larger dose than the british
national formulary
tell doctors to prescribe
and the conclusion uh from the
recovery trial was of course that it
didn't work and it was discontinued
in fact it was associated with an
increased length of hospital stable of
course
it looks like they were giving way too
much
uh wh o led solidarity trial again
giving very high doses 9
600 milligrams over 10 days and who
dropped it as well
didn't do further research on it because
they said it provided no benefit in
hospitalized patients with covered 19.
so what
what you could really call the two most
reputable research
bodies arguably in the world the world
health organization led
effort and the oxford for center
of evidence the oxford center for
evidence-based medicine
center seemed to get the dose wrong
now um
for the sake of balance so
let me just let me just say my working
conclusion now is that the low dose
hydroxychloroquine has efficacy based on
the belgium data
that seems to be what it's saying but
for balance
what i want to do is give you another
recent study
uh published just in july
remember the the belgium study was
published just on the 24th of august
that's bang up to date
but this is this is another study let's
look at this one uh and then we'll
finish for today hydroxychloroquine with
or without azithromycin
mild to moderate covered 19 again and
this was a new english journal of
medicine
based on work done in brazil
now this was a smaller scale study 55
hospitals in brazil it was randomized
that's good
it was open label now what does open
label mean
well very often in clinical trials we
like them to be blind now in a blind
trial
the person getting the medicine and the
person prescribing the medicine doesn't
know that they're getting the medicine
at all
they don't know whether they're getting
the medicine or whether they're getting
a placebo
i i i did this in in a study um
when i was a young staff nurse on
coronary care way back in the
uh a long time ago 1980
1988 i think it was it was called the
international study for infarct survival
and we were working out whether this
drug called streptokinase and
streptokinase in combination with
aspirin which is a clot busting drug
would work
so people would be agreed to come on the
trial
so would say to the people coming on the
trial come on the trial
and we'll give you the best available
treatment that's guaranteed
but there's a 50 chance you'll get this
new treatment as well which did turn out
to be brilliant by the way
the clock blasting drugs the the
thrombolytic drugs are absolutely
revolutionized corona care
um so you know if i was coming in with a
heart attack you'd say to me well you
get the best treatment we've got or
there's a 50
chance you'll get this extra treatment
so most people obviously went on the
trial
and then what happened was we went we
went to a box
and we had the we had the bags of fluid
because we gave it as intravenous bags
of fluid
and it had a number on it and we didn't
know whether whether it was the active
thrombolytic ingredient or whether it
was the um
a bag of salty water and and we just
gave it and we recorded everything
and it was only the people that had the
codes to that that would know so
me as the person giving it the doctors
prescribing it and the patient receiving
it
none of us knew where they were giving
the active thrombolytic ingredient or
whether they're giving a bag of salty
water we didn't know
that that's blind but this wasn't like
that
this was open label and obviously blind
is better but this was an open label one
so the prescribers and the patients knew
what they were getting
but they did have three groups and it
was controlled now
notice here and this is the trouble with
quite a few of these trials
quite a few of these trials um they're
actually based if you know if you're
doing a trial it's actually quite a lot
of work
it's a it's a lot of work so you know
recruiting 670 patients
is quite a lot the last research study i
did i don't i don't do much research now
but
i did this research study and i
recruited students from
the uk hong kong um cambodia
and kenya and i wanted to compare the
efficacy of
educational um educational
interventions in these different
cultures trying out the same educational
intervention in different cultures
and i think i recruited about 600
600 patients all together but i tell you
what that took some doing you know
that involved trips to cambodia and
trips to kenya i mean i was
teaching there anyway but um you know it
involved a lot of
travel a lot of work okay i didn't have
a team it was just me and
and people in the institutions there
that were kind enough to help me
but recruiting 600 patients with 600
students in my case was a lot of work
so for a study to recruit 667
isn't too bad but remember
we're much more likely to get valid data
from the larger numbers and the belgian
study had 8075 so the belgium study had
many more patients
therefore the validity of the data that
we're likely to get from the belgian
study
is likely to be much better it's likely
to be more valid
anyway let's keep going uh 504 patients
confirm with covered
now these were patients who weren't very
ill again they weren't the sickest
patients they're receiving no
supplementary oxygen
or a maximum of four liters per minute
now four liters per minute is
is is a is a low-ish dose um typically
it would start patients off on two
liters per minute that'd be the lowest
dose that you can give realistically
actually
very often give that with the nasal
cannula but for four liters per minute
would be
a relatively modest dose of oxygen a
relatively modest amount
so these weren't the sickest patients
they were that they were dealing with
here
and they had they had three groups
one to one to one standard care group
they recruited uh 229
uh standard care plus hydroxychloroquine
that's the second group so that's the
first group standard care
that's the control group really standard
care
plus uh hydroxychloroquine 400
milligrams twice daily
so a bit of a higher dose than the uh
bit of a higher dose than the dutch
study because that gave 400 milligrams
on the first day that only 200
milligrams
twice daily after that so a bit of a
higher dose uh 221 patients and then
standard care
plus hydroxychloroquine 400 milligrams
twice a day plus
azith azithromycin as well which as we
said
is known to have uh antiviral
well probable antiviral and
immunomodulating effects
because remember we don't want the
immune system to get out of control
because that's what causes the acute
respiratory stress
syndrome causing the alveoli to fill up
with fluid as you know if you watch
these
videos before now the results um
in in this uh brazilian study no
difference in the need for ventilation
no difference in the deaths no
difference in the thrombolytic
complications that's the little blood
clots that form in the blood vessels
no difference in the number of people
getting acute kidney injury that's
acute renal failure so they found no
difference between these three groups
but it's a much smaller scale
study it's only 667 not over
8 000 patients having said that you
would expect to see something but you
didn't
is there a contradiction here yeah there
does appear to be a contradiction here
um they examine the clinical status
after 15 days
uh standard care was bridged at one uh
hydroxychloroquine alone
uh patients did uh got 21 more
uh that they got a 20 uh 21
higher scale on on the adjudication
scale that they were using to
monitor how the patients had uh had done
and the higher the number
uh the worse the outcome on their scale
so that they were 21
21 more likely to do badly
so the hydroxychloroquine alone was
having a negative effect
and the hydroxychloroquine plus
azithromycin
their hazard ratio was 9.99
which means there was a one percent um a
one percent reduction
in poor outcomes so but
but but but the big but is neither of
these were significant
you know it's only when you reach the 95
significant value of that so they can be
ignored basically
it's not significant data it's not
significant data
i remember when i was doing my uh i did
a biology degree
and i did this really complicated study
on different things and
it was comparing one group against
another group and
you know there was nearly a change in
every group but it wasn't quite at the
95
level so it was really confusing so i
argued this
and i got the res with the assignment
back and like in big red letters all
over it
the examiner said do not argue from
non-significant data
do not argue from non-significant data
in other words if it's less than 95
percent
likely unless the 95 chance of the
genuine difference
we have to assume there's no difference
at all so very frustrating for
researchers but
um if it doesn't reach significance the
result's not significant by by
definition
it's uh it's no good and these didn't
reach significance
and in this study uh in brazil
they did find a pre-elongation of the uh
corrected uh
qt interval um now what
this is often talked about with
hydroxychloroquine with large doses
this is why it's so important to give
the right dose
because it's quite toxic
hydroxychloroquine and
hydroxychloroquine are quite toxic in
in higher doses if you give higher doses
of the chance of heart
not beating properly uh cut what we call
cardiac dysrhythmias
and a lot of people call them
arrhythmias but really they're
dysrhythmias
and fitting is another possibility so
what what they found and
several studies have shown that
pre-elongation of the qt interval
so i'll tell you what this is so in a
normal heart wave you have the p
wave um the p wave is the
contraction of the atrial myocardium
then you have the q
r and s like that and then you have the
uh
the t wave so that that's a normal
that's a normal heart rhythm so
p that's the q that's the q down there
that's the r uh p q
r that's the s and that's the t wave so
that's that's the normal heart wave so
that's the top chambers contracting
that's the bottom chambers contracting
and that's the
the bottom chambers electrically uh
going back to normal process called
repolarization
so what these studies found was
prolongation of the q
t interval so that's the q there that's
the t
there in other words that interval was
prolonged
indicating usually there's trouble with
the conduction
of electrical impulses through the heart
and of course if that's messed around
with too much
the heart will not be beating properly
and it will uh
potentially you can go into cardiac
arrest that's of course why we have to
give the right dose
so there was slightly more of this in
the the brazil study
but of course they were giving a fairly
high dose they were giving 400
milligrams
on day two on day three day four you
know they're giving 400 milligrams twice
a day all the way through to day seven
whereas in the uh the dutch study i've
got dutch there that's why i'm getting
produced
it's belgium
sorry if ever i've said dutch in this
study i've met belgium i get
holland and belgium mixed up it's the
belgium study
that we looked at um it's that one
loadout cyclops whenever i should have
studied yeah
yes it's definitely belgium isn't it so
this is
apologies to people in belgium if i've
said dutch but i meant i meant belgium
all the way through
um so in the belgian study um
that they only gave 200 milligrams and
200 milligrams
uh 200 milligrams twice a day on days
two to five
so the brazilian studies were giving a
significantly higher dose
so it's not too surprising they did get
some
no they're not saying it was a big study
but there was some prolongation of the
the qt interval
an elevated liver enzymes indicating the
liver didn't like the
the dose of the drug it was getting but
the conclusion of the brilliant study
amongst patients hospitalized with mild
to moderate carbon 19
the use of hydroxychloroquine alone or
with a xithromycin did not improve the
clinical stages at 15 days as compared
with standard care
now unlike the belgium study they didn't
carry this on
to 40 days which is disappointing
so there we go this study in belgium
is a strong indicator of efficacy
for correctly dosed
hydroxychloroquine
in hospitalized patients and it seemed
to have efficacy
that was quite significant
even if the treatment was started five
days after the patient's first
symptoms so
there we go that's that's interesting so
my conclusion is that
uh this study does provide substantial
evidence that low dose highly toxic
chloroquine
could be an effective treatment
so what needs to happen now is the
center for oxford-based medicine and the
world health organization need to go
back and look at this
and saying okay we got the dose wrong
last time let's do this studies again
with a proper dose this time
and find out if it is efficacious
it's just a pity all this time has been
um
has elapsed since since their
discontinued
hydroxychloroquine from there from their
trials
thank you for watching as always