What makes the SAIVE study so good?

Professor Aldous has frequently advocated the use of ivermectin for the treatment and prophylaxis of SARS-CoV-2 infection (covid-19) and has worked closely with front-line physicians in this field.  She explains that participants in the SAIVE trial were unvaccinated and had been exposed to a person with PCR-confirmed SARS-CoV-2 infection. The dosing of ivermectin – 200 micrograms per kilogram on the first day and 100 micrograms per kilogram for the next 27 days – was designed to emulate the slow-release injectable product that Medincell is developing. The results showed that there was a 72 per cent reduction in infections in participants who received ivermectin.

https://youtu.be/uzpxNfb2YZI

Ivermectin – is it safe and effective?

Ivermectin has two particularly important mechanisms of action in covid-19; it kills the virus and it prevents or reverses haemagglutination that otherwise leads to micro-clotting. “I would say that the best window to use ivermectin is at the beginning of the viral infection – [at the] infective stage”, she says. Had the drug been used in this way then there could have been a 58-59 per cent reduction in mortality, she notes.

https://youtu.be/tsm5wYmbpM0

TOGETHER trial shows positive effect for ivermectin

The TOGETHER trial, widely reported as showing that ivermectin was not effective in covid-19, actually showed a 58-59 percent reduction in mortality in the ivermectin treated group. Furthermore, the ivermectin was given “when people had at least seven days …. of being symptomatic; their viral phase had passed. That window where ivermectin would have done its best work was gone”, says Professor Aldous. Despite this late administration of the drug there was still a positive effect for ivermectin, she emphasises.

https://youtu.be/urfghlGVRK8

Addressing the totality of evidence for ivermectin

Randomised controlled trials (RCTs) alone are not the most efficient way to identify effective treatments using repurposed drugs, argues Professor Aldous. What is needed is a way to evaluate the ‘totality of evidence’. This would take into account laboratory studies, case reports, observational studies and RCTs, she says. It would also be in line with David Sackett’s original conception of evidence-base medicine, she notes.

https://youtu.be/fK1ocsEjHRg

How the totality of evidence (for ivermectin) informs clinical practice

The evidence supporting the use of ivermectin for covid-19 came together from a variety of sources to tell a compelling story. Laboratory studies showed that it was virucidal in vitro. Frontline clinicians in Zimbabwe, California and Nigeria all reported similar results – rapid recovery from oxygen desaturation. Further laboratory studies demonstrated the reversal of covid-induced haemagglutination and the SAIVE RCT now provides robust evidence that infection can be prevented.

https://youtu.be/GCcfOSgOFU4

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In 2020 a study from Australia reported that ivermectin kills the virus in a Petri dish (in vitro). Some commentators said that the concentrations of the drug were too high and could not be reached in the body (in vivo), however, the study was not designed to determine doses, notes Professor Aldous.  At that time dosage regimens for scabies were already established and another study showed that high doses were tolerable.

Next came reports of clinical experience from front-line physicians. “I worked with Dr Jackie Stone – we looked at a number of her patients where she was able to show how quickly the oxygen saturations improved as soon as she started her patients on an ivermectin containing regimen. ….  We had the same results from [Dr] Sabine Hazan in Malibu in the [United] States and from Dr Babalola in Nigeria.  So, the results of that study were basically repeated”, explains Professor Aldous.

This confirmed that ivermectin worked in clinical practice and could rapidly restore normal oxygen saturation.  The next step was to find out why this happened. A study by Boschi showed that covid viruses caused haemagglutination (micro-clotting). Adding ivermectin reversed the micro-clotting and pre-treatment of blood with ivermectin prevented micro-clotting. “So how does this explain what happened in Jackie’s clinic? Clearly, if you’ve got red blood cells clumping together they’re not going to be able to carry  the blood around. You’re going to get micro-clots forming, the lungs are not going to be able to work [if] you’ve got all this hemagglutination happening. If you give the patient ivermectin those little clots start to disperse …. the red blood cells can now carry on doing their job”, explains Professor Aldous.

In summary, Professor Aldous says: “So, now what do we have? We have a clinical observational paper, we have a laboratory experiment done right in the beginning, a more sophisticated laboratory experiment much later with more variants, not just the Wuhan variant. Now, finally, we’ve got the Medincell experiment which shows ivermectin definitely does prevent people from getting covid, so, if you look at the totality of evidence, you’re able to come to conclusions that will inform clinical practice.”

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Professor Aldous describes how evidence to support the use of ivermectin for covid-19 came together from a variety of sources. The drug had been in use for several decades and was already known to be safe in large doses. “Early on in the pandemic, in about April, we had Kylie Wagstaff’s group showing us that it killed the virus in a Petri dish… so why not try it?”, she says. There followed a number of case studies and comparative studies with mixed results. “It was only in the beginning of 2020  that I started monitoring the data and I started looking at all the data from January 2020 that has to do with ivermectin and covid-19. In October last year I could see that there was an almost equal amount of ‘absolutely yes, ivermectin works’ and ‘absolutely no, ivermectin doesn’t work’ and a whole lot in between where people said ‘we’re seeing signals that it will work – we just need more research’.”  Part of the reason for this was that researchers had realised that even if the results clearly showed a positive effect, without this caveat at the end of their papers they would not be published, she explains. “And that’s what has happened. Everybody has been saying, ‘Bring me one large randomised, controlled trial and I’ll change my mind’. Well, that is antiquated thinking; it’s thinking …. it’s a modern thing to do a randomised, controlled trial but it’s not appropriate in a pandemic”.

Considering all the evidence

“What is wrong with a good doctor, like Jackie Stone for example, reporting on what’s happening on her 37 patients where she has seen the blood oxygenation improve, she’s got the figures. Why is that data dismissed?”

“We should have been looking at the totality of evidence just as David Sackett – the father of evidence-based medicine – wanted it to be. Never once did he say a randomised, controlled trial was the gold standard but you’ve got to look at the totality of evidence”, says Professor Aldous.  She also believes that the oft-cited pyramidal diagram for the hierarchy of evidence has been misinterpreted. “People have changed what it was meant to be – an hierarchy of certainty. So, clearly, a randomized control trial has more certainty than a straight observational trial but people have misinterpreted that – in print and in textbooks – as being quality”, she says.

Professor Aldous suggests that what is needed is a way to take into account all the pieces of evidence that are available to build a more rounded picture of the way that a drug performs.  She plans to publish a proposed scheme for this in future.

There also needs to be a critical analysis of the design of some trials. “Many of those randomised, controlled trials that show negative results used ivermectin too late or in doses that were inappropriate. Some people have said ‘designed to fail’ – I don’t know if I’m that cynical, I just think people just didn’t know and this particular Medincell trial [SAIVE] shows us exactly where we should be using ivermectin”, she says. “In general, if you’re seeing a trend across the globe of people saying, ‘I’m using this drug and it’s working’, it’s not rubbish”, she adds.

In summary she says: “If we’ve got a 59 per cent reduction in mortality as the TOGETHER trial shows, we could have saved lives. If there’s a 72 per cent reduction in in morbidity, we could have saved working hours. So, the ‘type 2 error decision’ based on waiting for one large, randomised controlled trial – which might not be well designed – was wrong. We should have made a ‘type 1 error’ decision, tried it out, gathered the information, and it would have all been over a lot sooner”.

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The TOGETHER trial had 679 participants in each arm; 624 completed the intervention arm and only 288 completed the placebo arm. Nevertheless, mortality was calculated using the intention-to-treat (ITT) number. There were 24 deaths in the placebo group and 21 in the intervention group. “Let’s think about this – a school child can work this out – 21 out of 624 or 24 out of 288; which group has the higher death rate?” asks Professor Aldous.

She contacted the authors to seek clarification but received a “dismissive response”. Further efforts to find the original data were also unsuccessful. However, the fact remains that the published figures show “about a 59 per cent reduction in death rate ….  [with] a p-value of 0.0009”, she says. Furthermore, the ivermectin was given “when people had at least seven days – some of them – of being symptomatic; their viral phase had passed. That window where ivermectin would have done its best work was gone”, she explains. Despite this, there was still a positive effect for ivermectin, she emphasises. “The way it has been written and given to the world was supposed to be the coup de grace for ivermectin and I think those of us who can think for ourselves actually see that they showed it did work”, says Professor Aldous.

Beyond RCTs

Researchers and clinicians emphasise that RCTs alone cannot provide all the clinical evidence that is needed to make important decisions about the use of medicines.

Professor Aldous cites the example of penicillin, which did not go through a randomised, controlled trial. Discovered in the 1920s by Fleming, it was used to cure conjunctivitis in the 1930s. “In the early 1940s, with a very purified form, Fleming had permission to have it used in a moribund patient with meningitis. There was no cure -this patient was going to die – so he was administered this penicillin and that man lived. That particular clinical event was written up in a case study and then the War Room had a meeting based on that case study and within a couple of years there was enough penicillin for all the Allied Forces. And we are still using penicillin today”.

The need for RCTs was recognised and given greater urgency by events such as the thalidomide disaster. “We don’t ever want to repeat of that – and so randomised controlled trials started picking up ….. and as pharmaceutical companies got more and more sophisticated, they were able to use randomised, controlled trials for novel drug development and I believe that that is exactly where they are appropriate – in novel drug development”, concludes Professor Aldous.

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Professor Aldous has examined the safety of ivermectin carefully. “Right from the beginning I’ve looked at the safety and tolerability of the drug”, she says. The (WHO) VigiAccess database has not recorded any additions and there has been no increase over the 25 deaths reported long ago “so it’s a very safe drug”.

She recalls that early in the pandemic in South Africa “two members of a family took a very large dose of veterinary ivermectin…… and they ended up being hospitalised; the effects were transient – within a week they were fine”.

The possibility of long-term liver disease has been mentioned but does not appear to be supported by evidence “I’ve done my research – I’ve looked for the papers, I’ve looked in VigiAccess, I cannot find anything on severe liver damage. In fact, I think it’s one of the safest drugs we come across …… if you compare it to aspirin it’s a very safe drug, very well tolerated”, she says.

Clinical practice also bears this out: “As you know, people like [Dr] Jackie Stone would often use very high doses ….. She gave them high doses of ivermectin in order to get the [oxygen] desaturation sorted out and the worst side effect she saw there was blurred vision, which was transient”, says Professor Aldous.

Clinical effects of ivermectin

Some 20 different mechanisms of action have been described – some of which are direct effects on the virus whilst others “help the system to fight it”. Ivermectin also has anti-inflammatory effects.

Two particular mechanisms of action are important – the fact that it kills the virus  and that it either prevents hemagglutination or it reverses hemagglutination – as shown in the Boschi paper, says Professor Aldous.  “So I would say that  the best window to use Ivermectin is at the beginning of the viral infection – [at the] infective stage”, she adds.

In many trials the best window for ivermectin treatment had already passed when the treatment was started. Of course, there could still have been marginal improvements, because of the drug’s other actions, she acknowledges. “Use ivermectin right at the beginning and address the virus and then there’ll be no progression”, she emphasises.

It is difficult to say from the results of [the SAIVE] trial what would have happened had ivermectin been used routinely for early treatment of covid-19 from the early days of the pandemic. “It’s hard to say exactly how many people’s lives would have been saved because this trial was carried out during the Omicron phase, but if there were 72 per cent reduction in infections, it means that if we had given prophylaxis to many people they would not have gotten sick or they’d have got mildly sick – and if they didn’t get sick they wouldn’t have progressed to death”, says Professor Aldous.

The figures from Uttar Pradesh (India) where ivermectin was routinely used for early treatment and prophylaxis, bear this out she notes.

“Let’s forgive everybody for running around not knowing what was going on in 2020 but from 2021 we could have made a ‘type 1 error’ decision and started using ivermectin and prevented at least 72 percent of the disease. And if we go on figures that come from the TOGETHER trial ….we would’ve had a 58 per cent reduction in mortality”, she concludes.

Read and watch the full series on our website or on YouTube.

Professor Aldous has frequently advocated the use of ivermectin for the treatment and prophylaxis of SARS-CoV-2 infection (covid-19) and has worked closely with front-line physicians in this field.  The SAIVE trial evaluated the effectiveness of ivermectin for prevention of covid-19. She identifies several important features of SAIVE:

• There are 200 participants in each arm of the study
• The study is randomised, double-blind and placebo-controlled
• The medication in the placebo arm was matched to that in the intervention arm (which does not always happen)
• The study included only non-vaccinated participants – it was conducted in Bulgaria which has a low vaccination rate
• The participants had been exposed to a person with PCR-confirmed SARS-CoV-2 infection

In fact, “they took a lot of trouble to make sure that …… the participants had been exposed to the virus”, says Professor Aldous. Crucially, the company (Medincell) also established an independent US-based Data Monitoring Committee to oversee the trial. “For those people who are cynical about a company doing their own trial because there’s a conflict of interest ….. I think that the conflict of interest has been addressed with that”, she says.

The dosing of ivermectin – 200 micrograms per kilogram on the first day and 100 micrograms per kilogram for the next 27 days – was designed to emulate the slow-release injectable product that Medincell is developing. The medication was started after a participant had been exposed to a sick person. They were then monitored to see how many participants developed laboratory -confirmed SARS-CoV-2 infection.

The results showed that there was a 72 per cent reduction in infections in participants who received ivermectin.  Professor Aldous notes that the results have only been published in a press-release so far and there has, as yet, been no academic publication of the trial. Therefore, many questions remain.  She would like to know “at what date after they started taking the regimen did they start showing symptoms; when were they PCR-positive; if they were symptomatic, how long were they symptomatic”. Also, she is curious to find out what happened to the single participant who did not complete the placebo arm. “I’d like to know if they just went and got treatment because they weren’t feeling well”, she says. “There are lots of questions that will be answered when this paper comes out and I’m really looking forward to that”, she adds.

Read and watch the full series on our website or on YouTube.