Covid19Crusher's tweet letting me know about this study:

Brazilian 3-arm randomized no-control trial compares hydroxychloroquine / nitazoxanide / ivermectin in early treatment of 585 RT-PCR confirmed COVID outpatients. Not 1 hospitalization compared to a 16% case average nationally. Odds ratio: 0.000000. Hmm.

A few more points:
* Time to treat 3 days but time from symptom onset
* HCQ / NTZ / IVM equally efficacious. Hmm.
* ca. 80% of patient with vitamin D supplementation
* ca. 50% under spironolactone
* ca. 20% with vitamin C and/or Zinc

Hmm. Amazing...
Too good to be true?

That trial was not even the primary scientific objective of the authors who pursue an interesting androgenic treatment angle and wanted to select the best of the 3 studied drugs for a further RCT, called AndroCoV. Have they already solved Covid-19?

https://www.firstwordpharma.com/node/1735447?tsid=17

[Not C19C] Were the people actually sick? Did they do viral cultures to confirm? There’s a 95% asymptomatic rate pretty much everywhere now. When you account for presymptomatic you still get an awful lot of PCR positives that aren’t actually sick.

C19C:

87% symptomatic

[Not C19C]

In the other hand, similar results to Dr. Brian Tyson. 3 days on symptoms onset is very early, could that have contributed to the efficacy? And no doubt the 80% vitamin D is another positive advantage. Too good to be true, but not impossible.

Thanks C19C!

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Just something that caught my eye in the paper (https://www.researchsquare.com/article/rs-98106/v1):

To participate in the present prospective observational study, confirmed subjects had to fill the following inclusion criteria: 1. 18 years old and above; 2. Less than seven days since the beginning of symptoms; 3. Less than five days from the confirmation of COVID-19; 4. Lack of use or use in less than 72 hours of hydroxychloroquine, nitazoxanide and ivermectin; 5. Lack of previous use of glucocorticoids in the last seven days;

These patients may have used any of those drugs prior to acceptance to the study. I have not delved further yet, but that sounds like a significant confounding factor.

Up to 7 days since symptoms and 5 days since confirmation of COVID-19 is quite late, and according to their data a mean of 3 days time-to-treatment putting the participants at around day 6-8 of disease.

Not sure what to make of this study.

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This was a pilot study comparing HCQ, ivermectin and nitazoxanide, which resulted in the subsequent AndroCoV looking only at nitazoxanide. Bummer.

Is it a win for ivermectin? It IS in that none of the 110 patients advanced to serious disease. There's no control arm, though, raising the inevitable question "Would any have advanced without ivermectin?"

It's not a win for ivermectin, in that it was (very slightly) inferior to the other drugs by one criterion or another, never shining. And it lost the sweepstakes for which drug is the subject of the AndroCoV RCT.

I didn't learn very much, going through the PDF in detail. The study showed that all 3 drugs worked more-or-less equally well. There were muddy bits I didn't understand, esp. the inclusion criteria and the role of medication received before the trial began (no data about that was reported -- or I missed it). I don't understand what stage in the disease the patients were in when they first started treatment. Post-viral, is my guess. We (or at least I) think ivermectin works at all stages, but it's main thing is knocking down the virus, so post-viral misses its strength.

I'm not sure this is worth reading.

Notes from the PDF.

Treatment:

Hydroxychloroquine was given at a dose of 400mg/day for five days;

Nitazoxanide was given at a dose of 500mg, twice a day, for six days; and

Ivermectin was given at a dose of 0. 2mg/kg/day for three days.

Ivermectin only 3 days, compared against HCQ 5 days and Nitazoxanide twice a day, 6 days. Seems like an unfair comparison. Why didn't they do the same dosing schedule for all 3 drugs, since they were trying to compare their efficacy?

One of these drugs (exceptionally, two of them were used, except for the combination of ivermectin and nitazoxanide) was associated with azithromycin 500mg/day for five days.

I have no idea what that means. Did they ALL get AZT, or just one unnamed drug, which seems nonsensical. Anyone?

The drug was chosen in a quasi-random manner, i.e., hydroxychloroquine tended to be avoided in patients at higher risk for heart complications, drugs with previous history of intolerance were avoided, and also according to clinical judgement, availability, and individual medical history.

In other words, it was ad hoc, depending on a clinical assessment -- nothing like "random" as in "random controlled experiment. This is like the ICON study, where MDs gave out ivermectin if they wanted to, that study's huge flaw.

In case patients had already started on one of the three drugs, it was maintained, and adjustments in doses and inclusion of azithromycin were performed.

What? One of the inclusion criteria was "Lack of use or use in less than 72 hours of hydroxychloroquine, nitazoxanide and ivermectin". Were patients on HCQ 4 days before being enrolled, and therefore kept on HCQ? Why?

All of the reported data, with notations below each table that are really difficult to read. SHIT: imgur screwed up the order of the tables too. You can go to imgur to see the tables with readable-sized-font comments. Just right-click on the link and select "Open in another tab" (or your browser's equivalent).

The present prospective observational study combined the early detection of COVID-19 by suspecting in the presence of any symptom, not restricted to those typically described to occur in COVID-19, nor those that appears later in the disease, including anosmia, ageusia, fever and shortness of breath, with an open-label therapy using some of the most popular drugs claimed to be effective against COVID-19, particularly during the first stage.

I guess this referred to their recruitment process. From the Materials and Methods section:

Participants were recruited from social media and referred from other medical centers. Patients confirmed for COVID-19 with positive rtPCR-SARS-CoV-2 with fewer than seven days of symptoms and four days of treatment were included.

They were all (?) PCR+ for covid19. Some of them had as many as 4 days of treatment?

The large number of patients enrolled and treated (n = 585), with a virtual absence of dropout (0.3%), without occurrence of any hospitalization, mechanical ventilation, or death, shows that the pronounced differences when compared to untreated COVID-19 course are unlikely to be due have occurred randomly. The present findings reinforce the hypothesis of the protective effective of early pharmacological approaches when COVID-19 is detected after its early clinical signs.

It would if the population studies was clearer. A control are would have been REALLY helpful, to establish this assertion.

The investigation of androgenic phenotypes and chronic use of AA is critical importance to determine COVID-19 disease course (2, 9-11), since both have demonstrated to modulate the clinical presentation, including improvement of outcomes in COVID-19 in chronic use of AA (26). This finding is expected since TMPRSS-2, a cell surface protein that primes to the spike protein of SARS-CoV-2 and facilitates its cell entry, is strongly regulated by androgens, and is consequently underexpressed in chronic AA users. Hence, subgroup analyses of HA and non-HA females, AGA and non-AGA males, and AA users and non-users, i. e., without the influence of suppressed or enhanced TMPRSS-2 expression, could lead to different results. However, when adjusted for androgenic expression and only non-AA users, results remained similar, which reinforces the similarity between the efficacy of hydroxychloroquine, nitazoxanide and ivermectin.

Except you didn't present primary outcome data about antiandrogenic subjects, and where you did present data, it was distributed across the table, making it too difficult to see the differences, if any.

The apparently high rate of post-COVID syndrome, presented as a wide variety of physical and mental symptoms, that impair normal functionality (31-36), likely leading to a post-COVID public health issue, should become a key clinical outcome when evaluating and proposing interventions for patients with COVID-19. The persistence of symptoms or occurrence of new symptoms after COVID-19 cure in the population of the present study was as low as 1.5%, consistent throughout the different populations and drugs used, in contrast to the almost 90% of patients with manifestations after recovery, including 72.8% complaining of fatigue, when not pharmacologically approached during early COVID-19 (33).

Wow, 90%? Check that reference. Seems way to high?!

Also, control arm next time please.

For all outcomes, including the increasingly recognized post-COVID syndrome, early detection is likely the imperative aspect, confirming extensive previous descriptions and results (37). The lack of specificity of symptoms during the first days of COVID-19 makes its diagnosis challenging. Massive campaigns to educate and engage the population and healthcare workers to suspect of COVID-19 in the presence of any symptom, even unspecific ones, is highly recommended. In the spread use of masks, the likelihood of presenting URTI, cold, “u”, sore throat, sinusitis, and infections caused by other viruses is low. Consequently, symptoms that resemble any of these types of infections are more likely due to COVID19, and should be therefore suspected promptly.

This is a good point -- except in the US a lot of hospitals and clinics are overrun as it is.

If this study's subjects were all symptomatic, then they were all past or nearly past the period of viral proliferation, when these drugs are supposed to work best. (Not sure about NZT, don't know anything about it actually).

The choice was made without the full data, since the AndroCoV Trial (RCT) started one and half month later than the beginning of the observational study, when results were partial, although similar to the final ones presented herein.

Conclusion:

Hydroxychloroquine, nitazoxanide and ivermectin seem to be equally effective for COVID-19 in terms of clinical disease duration, viral duration, avoidance of hospitalization, mechanical ventilation and death, and to prevent post-COVID symptoms, at least when combined with azithromycin, vitamin C, vitamin D and zinc, with overwhelmingly differences, unlikely random, when compared to untreated COVID-19 population.

Between the three drugs, nitazoxanide was chosen for the AndroCoV randomized clinical trial due to its strong broad spectrum antiviral activity, plausibility to act as an anti-COVID agent, and safety profile.

Boo. Hiss. You suck!

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The author of this twitter thread puts forward the idea that the success of all three drugs may be attributable to vitamin D. 82.3% of study subjects took D.

The thread rolled up.

I replied:

Ivermectin has shown good efficacy against COVID-19. "No advancement of disease" is typical. I know less about HCQ and nothing about Nitazoxanide. It's certainly possible that all three work well.

Your point about Vitamin D remains though!

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