Jury’s in for ivermectin: “No clinical significance.”

At last, one of the largest and most rigorous clinical trials to test ivermectin as a COVID treatment has published its results in the prestigious New England Journal of Medicine.

The fervent belief for many was that ivermectin – originally a worming medication – would protect infected people from progressing to severe disease requiring hospitalisation.

The trial found that ivermectin given in the first seven days after symptoms had no significant effect.

For those in the know, the finding comes as little surprise. The so-called TOGETHER trial reported its primary results in seminars to other scientists and policy makers in early August last year.

The question is why it has taken so long to publish those results for the rest of us. The lack of clarity over the effectiveness of ivermectin has wreaked havoc. Many have foregone vaccination and even refused tested medical treatments, preferring to take ivermectin at unsafe high doses or even veterinary pastes in the belief that it was a cure. These beliefs have been propped up by doctors around the world, including those in Britain’s BIRD, the US-based Front Line COVID Critical Care Alliance, or Thomas Borody and colleagues in Australia.

“It is puzzling that the important and completed ivermectin arm has not reported its results [till now], says Paul Glasziou ,a professor at the Institute for Evidence Based Healthcare at Bond University, Gold Coast. “The use of preprints to rapidly provide clinicians and policymakers with results is vital for uptake of effective treatments as well as stopping ineffective and potentially dangerous treatments like ivermectin.”

When the COVID pandemic hit in the early months of 2020, doctors were helpless to treat the patients dying in overflowing emergency rooms. A number of randomised clinical trials (RCTs) were urgently rolled out to test drugs on the shelf – so-called ‘repurposed drugs’. These included everything from HIV drugs to anti-inflammatory medications to tamp down friendly fire from a raging immune system.

The fastest and most successful trial – dubbed RECOVERY and based at Oxford –  focused on saving the lives of hospitalised patients whose death rate was 25% or 40% if they needed to be placed on ventilators.

In June 2020 RECOVERY posted a preprint – a paper hosted by a website but yet to be peer reviewed and published in a journal. It reported that the inexpensive steroid dexamethasone could cut the deaths of those on ventilators by a third. The rapid dissemination of the results by preprint is estimated to have saved the lives of thousands of people.

Another RECOVERY preprint also saved lives by reporting that the repurposed malaria and rheumatoid arthritis drug hydroxychloroquine – much feted by Donald Trump – not only failed to help hospitalised patients but appeared to make them worse. “Patients allocated to hydroxychloroquine were less likely to be discharged from hospital alive within 28 days,” the preprint reported.

The TOGETHER trial led by Ed Mills at McMaster University in Ontario, Canada, was initiated in June 2020. It also tested repurposed drugs but focussed earlier, in patients who were still in the first week of their illness. The idea was to find medications that would stop them going to hospital, to contain COVID as the mild-ish disease that was experienced by 90% of patients. Unlike RECOVERY, which sourced patients from British hospitals at the height of their pandemic, the TOGETHER trial sourced its patients from Brazil. This was necessary because the pandemic seems to move in waves and by the time the time RECOVERY started, the first wave in Canada had moved on, leaving few patients to recruit to the study.

TOGETHER tested some of the same drugs as RECOVERY for infected people to use at home, including hydroxychloroquine and the HIV drug combination lopinavir/ritonavir. They were not effective, as reported in a paper published in the Journal of the American Medical Association in April 2021.

Ivermectin was not included in the initial line-up of repurposed drugs. TOGETHER team member Craig Rayner, a clinical pharmacologist affiliated with the US-based company Certara that provides scientific advice to drug developers, modelled the effective drug doses for the trial.  Since the ivermectin dose required to kill the virus was more than 20 times the maximum approved dose, he advised against it.

But by mid 2020, ivermectin had replaced hydroxychloroquine as a popular COVID ‘cure’. Some trials showed it was effective; other didn’t – not a surprising situation in the early stages of testing of a drug. Expert pharmacologists like Andrew McLachlan at the University of Sydney declared a state of clinical ‘equipoise’, meaning the jury was out. Larger, gold standard RCTs were needed. (At the time, it had not yet been revealed that many of the studies showing ivermectin was effective were fraudulent.)

Given the situation on the ground, the TOGETHER team decided to include ivermectin in their trial. “We had an obligation,” says Rayner. “We realised the answer was unknown.”

The triallists recruited 3515 Brazilian patients from 12 health centres in the state of Minas Gerais. To raise their chances of detecting an ivermectin effect, the patients had to have at least one risk factor for serious disease, such as obesity or diabetes. These recruits were randomly allocated into different arms of the trial to test a number of different repurposed drugs against a placebo. The ivermectin arm treated 679 people and gave 679 people a placebo.

Based on what appeared to be positive findings from smaller trials, ivermectin was used at a cumulative dose six times higher than the maximum approved dose – 400 micrograms per kg of body weight per day for three days. The maximum dose that’s prescribed for the parasitic disease strongyloidiasis is a single dose of 200 microgram per kg of body weight. The measurement endpoint for the trial was hospitalisation 28 days after treatment by the drug.

By the beginning of August 2021, the researchers had their results. Ivermectin did not reduce the risk of hospitalisation. By contrast the cheap antidepressant drug fluvoxamine did, reducing the risk of hospitalisation by 30%.

So, why did TOGETHER take until the end of March 2022 to deliver the coup de grace for ivermectin? RECOVERY by contrast delivered its verdict for hydroxychloroquine in July 2020, letting the world know it was pointless and dangerous to use it as a treatment for COVID.

One reason is that the TOGETHER trial had a much tougher remit than RECOVERY.

RECOVERY tested hospitalised patients, who were easy to find being ‘captive’ in their hospital beds. Their death rate of 25% also made it easy to achieve statistically significant results.

By contrast TOGETHER had to rope in the mildly ill from out in the community within seven days of their first symptoms. And given only 10% of them would ever develop severe disease, they needed to be picky, selecting those with a risk factor for severe disease such as obesity or diabetes. “We needed to have the potential to detect an effect,” said Mills.

Moreover, while RECOVERY managed to roll out at lightning speed to catch the first COVID wave in the UK, by the time TOGETHER rolled out Canada’s COVID wave had receded, so they had to recruit in Brazil. And here they ran up against the problem of finding people who weren’t already self-medicating with ivermectin. That was partly circumvented by running the trial in Minas Gerais, a state in southeast Brazil where the use was not as widespread, says Rayner.

However, once the TOGETHER group overcame all these obstacles, why did they not publish a preprint like RECOVERY?

Mills says they decided to go the route of publishing in a major journal and that they did ‘air’ the data in talks.

But journalists find it challenging to report on unpublished data since the scientists they rely on to provide independent opinions are loathe to comment on unpublished data.

And the airing of the TOGETHER results did not have the necessary force to quell a degree of ivermectin hysteria that was seeing people eat veterinary worming pastes. In late August, the US FDA felt compelled to tweet: “You are not a horse. You are not a cow. Seriously, y’all. Stop it. … Using the Drug ivermectin to treat COVID-19 can be dangerous and even lethal.”

Rayner adds they did not expect it would take eight months till publication and were bound not to disclose a publication date or discuss the paper with journalists. “Had we known it would take this long, we might have considered a different route,” he says.

Another reason for keeping their data out of the limelight till now is that the TOGETHER scientists’ reward for carefully carrying out these difficult trials has been harassment and threats from ivermectin devotees. “This is not a matter of science but psychology,” says Mills.

“It’s not unusual to see a death threat in my inbox,” adds Rayner. “I’ve had to change my phone number. It’s pretty traumatising. We’re all feeling that way.”

Being under siege has left the researchers media shy.

“This report was not something I wanted to get ahead of. I fear what the release of the paper will bring,” says Rayner.

The secrecy and drawn-out reporting of ivermectin trials is not limited to the McMasters group. Chris Butler, the leader of the ‘Principle’ ivermectin trial at Oxford, is similarly tight-lipped as is the leader of an NIH trial known as Activ-6.

Neither of these groups responded to this journalist’s inquiry as to an expected report date.

Perhaps these trials, which are based in the in the UK and US, have also found it difficult to recruit enough patients to get a statistically meaningful result.

But their results, based in Western populations, will be important to compare to those of TOGETHER.

Because TOGETHER did actually find a small, but not statistically significant effect, of ivermectin on hospitalisation. Could it be a true but tiny signal in the noise? Mills suspects that in some Brazilian patients, ivermectin was actually treating the underlying parasitic infections – and that improved the person’s ability to fight COVID. That’s a theory suggested by this recent analysis. If that’s the case, this tiny effect of ivermectin would be restricted to people who are fighting parasitic infections.

But we will have to wait – again – for the PRINCIPLE and NIH trials to be sure.

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