When the COVID-19 pandemic took off in full force in 2020, and the first vaccines were introduced at the end of 2020 and into 2021, there was heated debate about the use of the antiparasitic agent ivermectin for both prevention and treatment of COVID-19. In some early studies, it appeared to have an effect, and in some circles critical of vaccines, ivermectin was hailed as a miracle drug.
But that was then. Since then, more and better research has been done, so what is the status today?
Early studies were poor
To summarise, the previous positive studies on the use of ivermectin as a preventive or curative treatment for COVID-19 were mostly weak studies. They were usually only based on observations and case studies, with relatively few patients.
To really know if a treatment works, you need randomised controlled trials (RCTs) of a certain size. You need to compare the drug being tested against a group receiving a placebo (or another standard treatment), and these must be randomised so that other variables that may play a role, such as age, gender, disease severity, general health status, etc. are "zeroed out" between the different groups.
Only then can you know whether the treatment is actually working or not.
It also became clear early on that several of the allegedly positive ivermectin studies were either falsifications, i.e. the data were manipulated and/or fabricated, that the studies had simply never taken place, or they were of such poor quality that they were completely worthless.
An early meta-analysis by Bryant et al from 2021, which analysed these early studies, nevertheless concluded that ivermectin was effective against COVID- 19:
Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.
A similar meta-analysis from the same year by Hill et al also found a similarly positive result.
But on closer inspection, there was a fly in the ointment. A number of epidemiologists and researchers scrutinised the studies included in this meta-analysis, and what they found was shocking.
Elgazzar et al
An Egyptian study, which contributed to much of the positive effect in the meta-analyses, had major flaws according to a student who happened to be assigned to analyse this study.
It turned out that much of the text in the study was simply copied from various press releases about COVID-19, and then run through a "search and replace" function in a word processor on certain essential words and concepts to make them seem relevant, which led to some meaningless sentences and ridiculous errors.
But worse than that, the patient data did not match what the study claimed about the study participants. The study claimed to include patients from 18-80 years of age, but included several patients under the age of 18.
The authors of the article claimed that the study was conducted between June 8th and September 20th of 2020, but most of the patients who died were admitted to hospital and died before June 8th, and therefore cannot have been part of the data. One patient was also listed as having been discharged from hospital on June 31st, 2020 - a date that does not exist.
All of this may be dismissed as "sloppy errors", but it got worse. The research article claimed that four out of every hundred patients in the group that received standard treatment, i.e. not ivermectin, supposedly died from mild to moderate COVID-19. However, in the raw data, the actual number of deaths in this group was zero.
Similarly, it was found that while the article claimed that only two of the patients treated with ivermectin died from severe COVID-19, the raw data showed that the number was actually four.
The researchers behind the Egyptian study were therefore sent a request asking them to explain this, but never responded. This prompted several experts to scrutinise the study, and the findings were summarised in this article. One of the most serious findings was an obvious falsification of data:
“The main error is that at least 79 of the patient records are obvious clones of other records,” Brown told the Guardian. “It’s certainly the hardest to explain away as innocent error, especially since the clones aren’t even pure copies. There are signs that they have tried to change one or two fields to make them look more natural.”
In other words: The entire study was falsified. And this was one of the largest studies on ivermectin; a study that had been touted as the ultimate proof of how amazing ivermectin was in the treatment of covid sufferers.
Problems were also found with at least one other study included in the two previously mentioned meta-analyses, and as these two studies drove the positive result in the meta-analyses, they ended up showing zero effect of ivermectin when these spurious studies were later excluded. One of these meta-analyses was later withdrawn.
These blunders by ivermectin enthusiasts were discussed in several articles, including on Retraction Watch, and not least by epidemiologist Gideon Meyerowitz-Katz, who has written extensively about these poor ivermectin studies. I have also reviewed several of these in previous blog posts about ivermectin (in my Norwegian blog).
What is the status today?
However, since then, a number of RCTs have been conducted so that we can form a more reliable picture of the effect.
As early as April 2022, Cochrane conducted a meta-analysis of the research on ivermectin as a treatment for COVID-19. They found 11 randomised, placebo-controlled trials of sufficient quality, with a total of around 3,400 patients, and they concluded as follows:
For outpatients, there is currently low‐ to high‐certainty evidence that ivermectin has no beneficial effect for people with COVID‐19. Based on the very low‐certainty evidence for inpatients, we are still uncertain whether ivermectin prevents death or clinical worsening or increases serious adverse events, while there is low‐certainty evidence that it has no beneficial effect regarding clinical improvement, viral clearance and adverse events. No evidence is available on ivermectin to prevent SARS‐CoV‐2 infection.
In other words: There was very little evidence that ivermectin had any effect in the treatment of COVID-19, and no evidence that it had a preventive effect.
Since Cochrane's analysis, several large, good RCTs have been published. One of them was published in March 2022. It included around 3,500 patients with COVID-19 in Brazil, and concluded as follows:
Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19.
This was the first truly large RCT to investigate this, and it was resoundingly negative. No effect of ivermectin was found.
In August of the same year, a new large RCT looked at just over 1,400 patients and tested whether any of the three drugs metformin, ivermectin and fluvoxamine could work through early treatment of COVID-19. Here, too, the conclusion was negative:
None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalisation, or death associated with Covid-19.
This was followed by a new RCT in October that included 1,800 COVID-19 patients who were randomised to receive either early treatment with ivermectin or placebo, and again with discouraging results:
Among outpatients with mild to moderate COVID-19, treatment with ivermectin, compared with placebo, did not significantly improve time to recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19.
But even with three negative, large RCTs, some people still believed that these studies were only negative because either too low doses of ivermectin had been used, or treatment had been given for too short a period. Therefore, another large study was recently conducted that increased the dose and duration of treatment.
This was published earlier this year (2023), with the following conclusion:
Among outpatients with mild to moderate COVID-19, treatment with ivermectin, with a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo did not improve time to sustained recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19.
Negative again.
Conclusion
This should bring this discussion to a close.
What we know from the research world, is that more often than not, early, low-quality studies turn out to have either an exaggerated or incorrect result when larger and better studies are later conducted.
There is a much greater chance of finding positive results when you have few controls, no placebo group, few participants, or the study is not pre-registered. As more robust studies are done, the trend will therefore generally always be in a negative direction when a treatment does not work. The better the quality of the study, the smaller the effect will be.
We see a clear example of this in the ivermectin vs covid research. The very early, positive studies were not controlled trials, only small observational studies. Later a few small RCTs were done, but these still were very poor and in at least one case a pure falsification. Eventually, there were some larger controlled studies, and the effect became more uncertain. Finally, there were the large, robust RCTs that have tested the use of ivermectin at different doses and durations in large groups of patiens, but all of them have shown zero effect.
If there was a real positive treatment effect with ivermectin against COVID-19, this trend would not be seen. We therefore should probably not except any positive data to appear if even larger and better studies are done in the future. The fact that the positive result disappears when larger and better studies are conducted demonstrates quite conclusively that the treatment is ineffective.
Ivermectin does not work against COVID-19. Unfortunately. It would be fantastic if it worked against COVID-19 because it is an affordable and simple treatment that has been extremely effective against parasitic infections, which is what the drug was originally developed for.
But against coronavirus, it has no effect.
