Scrutable

Posted: **Fri Mar 20, 2020 2:45 pm**

It appears from this paper that hydroxychloroquine might offer an effective treatment.

Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial. International Journal of Antimicrobial Agents – In Press 17 March 2020 – DOI : 10.1016/j.ijantimicag.2020.105949

Results
Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination.

Conclusion
Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.

(from virology blog (2020-03-19): Hydroxychloroquine reduces viral load in COVID-19 patients )

Posted: **Sun Mar 22, 2020 1:17 am**

That paper is getting torn apart on medRxiv and PubPeer right now.

Some highlights:
- My own modest contribution showing that all the p values in Table 2 appear to be half as big as they should be.
- The chi-square/Fisher's exact test analyses are not appropriate for a repeated-measures study.
- The control group appears to have been at least partly recruited at a different site.
- Whatever test they were using for signs of the virus clearly had poor sensitivity, as there were several cases of people testing positive, then negative, then positive again across the period of the trial.
- The timeline for ethical approval and 14 days of data collection doesn't seem to fit.
- Secondary outcomes are defined but not reported.
- Worst of all, of the 26 patients who started off in the intervention group, six were excluded from the analyses, including three who got worse to the point that they needed to be moved to the ICU and one who died. Treating people who die from the disease that you're trying to cure as if they just dropped out is what one might term an "innovative" approach to trial design.

Despite all this, the preprint was peer-reviewed and published within about 48 hours. Doubtless the fact that the editor-in-chief of the journal is one of the study authors had nothing to do with this.

Posted: **Sun Mar 22, 2020 11:54 am**

Thank-you for that update, sTeamTraen.

It's great to have the resources available around here to help sort the wheat from the chaff. I'm sorry I wasn't able to do that myself.

Posted: **Mon Mar 23, 2020 8:00 pm**

Anyone know anything about the Favipiravir trials happening in Japan? Seen some news stories, not come across any papers

CF

Posted: **Mon Mar 23, 2020 9:29 pm**

sTeamTraen wrote: Sun Mar 22, 2020 1:17 am That paper is getting torn apart on medRxiv and PubPeer right now.

Some highlights:
- My own modest contribution showing that all the p values in Table 2 appear to be half as big as they should be.
- The chi-square/Fisher's exact test analyses are not appropriate for a repeated-measures study.
- The control group appears to have been at least partly recruited at a different site.
- Whatever test they were using for signs of the virus clearly had poor sensitivity, as there were several cases of people testing positive, then negative, then positive again across the period of the trial.
- The timeline for ethical approval and 14 days of data collection doesn't seem to fit.
- Secondary outcomes are defined but not reported.
- Worst of all, of the 26 patients who started off in the intervention group, six were excluded from the analyses, including three who got worse to the point that they needed to be moved to the ICU and one who died. Treating people who die from the disease that you're trying to cure as if they just dropped out is what one might term an "innovative" approach to trial design.

Despite all this, the preprint was peer-reviewed and published within about 48 hours. Doubtless the fact that the editor-in-chief of the journal is one of the study authors had nothing to do with this.

Review here:

Statistical review of Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. March 23, 2020 DOI:10.5281/zenodo.37241 Dahly, Darren; Gates, Simon; Morris, Tim

It is not glowingly positive.

Posted: **Mon Mar 23, 2020 9:35 pm**

If hydroxychloroquine turns out to be ineffective it'll be a particularly bitter irony that the hype has already produced new victims who've overdosed by self-medicating with chloroquine.

https://edition.cnn.com/2020/03/23/afri ... index.html

Posted: **Tue Mar 24, 2020 1:47 am**

The PubPeer thread is here.

Also there's this, which is very worrying: 10,000 units of chloroquine will be distributed in NYC tomorrow, Trump says. The main backers of CQ or HCQ seem to be techbros, Trump supporters, and the extremely gullible, to the extent that those are distinct categories anyway.

Posted: **Tue Mar 24, 2020 11:36 am**

This trial will eventually tell what, if anything, is an effective treatment

Posted: **Wed Mar 25, 2020 9:43 am**

tom p wrote: Tue Mar 24, 2020 11:36 am This trial will eventually tell what, if anything, is an effective treatment

That trial seems to have outcome measures that people are actually interested in, unlike the French one which only measured the evolution of viral load. One explanation for the French results may be that because of the non-randomised nature of the trial, patients in the treatment group were simply further along the recovery path at their entry into the trial. See https://www.infranken.de/ratgeber/malar ... 83,4981490 ((in German, but browsers will translate).

Posted: **Wed Mar 25, 2020 5:34 pm**

Quite a long list of trials listed here;

https://www.clinicaltrialsarena.com/ana ... cov-drugs/

Posted: **Thu Mar 26, 2020 9:33 pm**

EACLucifer wrote: Wed Mar 25, 2020 5:34 pm Quite a long list of trials listed here;

https://www.clinicaltrialsarena.com/ana ... cov-drugs/

Thanks for that.

If I may display my ignorance here: is there a reason why, at present, it appears no-one is looking at making monocolonal antibodies to directly attack the virus in vivo as a therapy?

This is an old article: Nat Biotechnol. 2007 Dec;25(12):1421-34. : The growth and potential of human antiviral monoclonal antibody therapeutics. DOI: 10.1038/nbt1363

And this recent publication shows promise in Rhesus monkeys:

Immunity. 2019 Mar 19;50(3):567-575.e5. doi: 10.1016/j.immuni.2019.02.005. Epub 2019 Mar 5. : Adeno-Associated Virus Delivery of Anti-HIV Monoclonal Antibodies Can Drive Long-Term Virologic Suppression.

So obviously, they are not a magic bullet. But I don't understand why not, and there is probably a simple reason for it.

Posted: **Fri Mar 27, 2020 12:56 am**

This preprint also likes the look of monoclonal antibodies.

But a friend tells me that they are difficult and expensive to make in bulk.

Posted: **Fri Mar 27, 2020 2:06 am**

The always-entertaining Leonid Schneider has blogged about Raoult. Spoiler: He's not a big fan.

Posted: **Fri Mar 27, 2020 2:51 pm**

sTeamTraen wrote: Fri Mar 27, 2020 12:56 am This preprint also likes the look of monoclonal antibodies.

But a friend tells me that they are difficult and expensive to make in bulk.

this is why.
plus risk of mad side fx even at astonishingly low doses

Posted: **Fri Mar 27, 2020 4:02 pm**

tom p wrote: Fri Mar 27, 2020 2:51 pm
sTeamTraen wrote: Fri Mar 27, 2020 12:56 am This preprint also likes the look of monoclonal antibodies.

But a friend tells me that they are difficult and expensive to make in bulk.
this is why.
plus risk of mad side fx even at astonishingly low doses

Ah yes. You triggered a memory: "In its first human clinical trials, it caused catastrophic systemic organ failures in the subjects, despite being administered at a supposed sub-clinical dose of 0.1 mg per kg; some 500 times lower than the dose found safe in animals...All of the men were reported to have experienced severe cytokine release syndrome" - trial of Theralizumab.

Posted: **Wed Apr 01, 2020 8:47 pm**

Some suggestions that Bacillus Calmette–Guérin vaccine may mitigate some of the effects of SARS-CoV2.

This vaccine has never been routinely administered in Italy.

Posted: **Thu Apr 02, 2020 10:00 pm**

I have seen a rumour going round in French scientific circles that one of the ongoing trials of existing medicines is about to report spectacularly good results. The trial description (no results yet AFAIK, good or meh) is under this Spoiler link. You will maybe get why I did that when you see the name of the drug in question.

Spoiler:

Posted: **Thu Apr 02, 2020 11:21 pm**

shpalman wrote: Wed Apr 01, 2020 8:47 pm Some suggestions that Bacillus Calmette–Guérin vaccine may mitigate some of the effects of SARS-CoV2.

Is that the TB vaccine we all got as kids in the UK and that anyone my kids' ages or younger didn't get because the NHS stopped giving it? If it is, I'm going to be really pissed off that I gave up trying to find somewhere that would do it privately....

Of course, maybe not getting TB just helps with long term lung health and that makes you less susceptible.

Anyhoo... Came to ask what people think of this news story about masks:

https://www.bbc.co.uk/news/science-environment-52126735

I followed the link to the journal article. Seemed to make sense. Thought the bit in the BBC story about China finding virus particles in air conditioning was interesting as I've been thinking something like that might explain the rapid spread through cruise ships. But so might tests with high false negatives, I suppose, or sloppy quarantine protocols.

Posted: **Fri Apr 03, 2020 9:30 am**

raven wrote: Thu Apr 02, 2020 11:21 pm
shpalman wrote: Wed Apr 01, 2020 8:47 pm Some suggestions that Bacillus Calmette–Guérin vaccine may mitigate some of the effects of SARS-CoV2.
Is that the TB vaccine we all got as kids in the UK and that anyone my kids' ages or younger didn't get because the NHS stopped giving it? If it is, I'm going to be really pissed off that I gave up trying to find somewhere that would do it privately....

Of course, maybe not getting TB just helps with long term lung health and that makes you less susceptible.

Yes it is

Posted: **Fri Apr 03, 2020 10:13 am**

tom p wrote: Fri Apr 03, 2020 9:30 am
raven wrote: Thu Apr 02, 2020 11:21 pm
shpalman wrote: Wed Apr 01, 2020 8:47 pm Some suggestions that Bacillus Calmette–Guérin vaccine may mitigate some of the effects of SARS-CoV2.
Is that the TB vaccine we all got as kids in the UK and that anyone my kids' ages or younger didn't get because the NHS stopped giving it? If it is, I'm going to be really pissed off that I gave up trying to find somewhere that would do it privately....

Of course, maybe not getting TB just helps with long term lung health and that makes you less susceptible.
Yes it is

There's an amateur but enthusiastic analysis at https://www.jsatonotes.com/2020/03/if-i ... stral.html

I'm just not sure if the lack of reported cases in Russia is due to them using an older version of the vaccine, or rather due to them just pretending not to have cases.

Posted: **Fri Apr 03, 2020 11:20 am**

tom p wrote: Fri Mar 27, 2020 2:51 pm
sTeamTraen wrote: Fri Mar 27, 2020 12:56 am This preprint also likes the look of monoclonal antibodies.

But a friend tells me that they are difficult and expensive to make in bulk.
this is why.
plus risk of mad side fx even at astonishingly low doses

The search for Covid treatments using small molecule drugs has been more a case of drug repurposing, not novel discovery. Basically, taking the inventory of stuff we have already and throwing it at the virus.

The anti-viral mAb field is a step behind, because it's working on finding new antibodies, so starting completely from scratch and inevitably this is going to be slower. It's not just a case of finding an antibody, but also working out how to manufacture it at scale at suitable quality for therapeutic use.

Having said, I suspect people are looking at the existing toolbox to see if anything might fit. The most severe patients appear to develop something akin to lung fibrosis, which eventually blocks oxygen crossing into the bloodstream, and there are some monoclonals already in development for other conditions that might help counteract this. So less of a case of targeting the virus itself, more of blocking the damage to the lungs. Early days though...

Posted: **Fri Apr 03, 2020 7:02 pm**

shpalman wrote: Fri Apr 03, 2020 10:13 am
tom p wrote: Fri Apr 03, 2020 9:30 am
raven wrote: Thu Apr 02, 2020 11:21 pm

Is that the TB vaccine we all got as kids in the UK and that anyone my kids' ages or younger didn't get because the NHS stopped giving it? If it is, I'm going to be really pissed off that I gave up trying to find somewhere that would do it privately....

Of course, maybe not getting TB just helps with long term lung health and that makes you less susceptible.
Yes it is
There's an amateur but enthusiastic analysis at https://www.jsatonotes.com/2020/03/if-i ... stral.html

I'm just not sure if the lack of reported cases in Russia is due to them using an older version of the vaccine, or rather due to them just pretending not to have cases.

I'd lay money on Russia fudging the figures.

Just as I'm not 100% sure that the DPRK is completely free of COVID-19

Posted: **Fri Apr 03, 2020 7:51 pm**

jimbob wrote: Fri Apr 03, 2020 7:02 pm
shpalman wrote: Fri Apr 03, 2020 10:13 am
tom p wrote: Fri Apr 03, 2020 9:30 am
Yes it is
There's an amateur but enthusiastic analysis at https://www.jsatonotes.com/2020/03/if-i ... stral.html

I'm just not sure if the lack of reported cases in Russia is due to them using an older version of the vaccine, or rather due to them just pretending not to have cases.
I'd lay money on Russia fudging the figures.

Just as I'm not 100% sure that the DPRK is completely free of COVID-19

I'm sure they've found a good way to get rid of any symptomatic cases.

Posted: **Sat Apr 04, 2020 5:01 pm**

It would be interesting if both BCG and Thalidomide are effective against leprosy: One wonders what biochemistry is shared by SARS-CoV-2 and Mycobacterium leprae?

Posted: **Sat Apr 04, 2020 5:54 pm**

Bird on a Fire wrote: Fri Apr 03, 2020 7:51 pm
jimbob wrote: Fri Apr 03, 2020 7:02 pm Just as I'm not 100% sure that the DPRK is completely free of COVID-19
I'm sure they've found a good way to get rid of any symptomatic cases.

There was a joke circulating about this:

North Korea COVID-19 cases

18 March 08:15 1
18 March 08:22 0
18 March 12:44 1
18 March 13:07 0
19 March 10:04 1
19 March 10:18 0

etc

Scrutable

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