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According to Dr. Edward Mills, the TOGETHER Trial is one of the largest randomized clinical trials in the world evaluating the effectiveness of repurposed drugs, such as ivermectin, in the early treatment of COVID-19.
Mills is the principal investigator in the trial and he’s also an associate professor in the Department of Health and Research Methods, Evidence, and Impact at McMaster University in Hamilton, Ontario. He additionally works for Cytel, where he designs clinical trials mainly for the Bill & Melinda Gates Foundation. Cytel has also produced the “COVID-19 Clinical Trial Tracker,” where information about clinical trials taking place around the world are searchable by treatment type.
“Although COVID-19 vaccines are being rolled out across Canada, the US, and Western Europe, for low- and middle-income countries, it may be years before vaccines are universally available. For this reason, the TOGETHER Trial was created to evaluate the effectiveness of cheap, widely available drugs in low- and middle-income countries that can be repurposed for COVID-19,” reads the Trial’s news release.
The current clinical trial, which has been underway in Brazil since June 2020, has recruited 2,600 patients and has used what’s called a “flexible platform” trial design, which allows additional medications or agents to be added and tested. If an intervention is shown to be effective in treating COVID-19, the design allows the replacement of the placebo group with the effective intervention.
“The majority of my trials tend to happen in low-income settings, but because of the nature of this pandemic I’ve been pulled into trials here in North America, Europe, and around the world,” says Mills in an interview.
Asked about why patients weren’t recruited here in Canada, Mills explains that “conducting clinical trials in Canada is almost impossible because Canada does not have existing networks for collaboration on clinical trials beyond informal networks built on social relationships of investigators. The UK, on the other hand, can explain its successes with clinical trials as hospitals and clinics are mandated to participate in clinical research.”
“Secondly we just don’t have the rates of infection occurring in Canada that would warrant getting as large a sample size,” he says.
In Canada, the practice of medicine is subject to provincial and territorial oversight. According to Nova Scotia Health, ivermectin is not currently recommended in Nova Scotia for the treatment of COVID-19 as per recommendations from the COVID-19 Therapeutics and Prophylactics Advisory Group. 1
The TOGETHER Trial received funding from the Bill and Melinda Gates Foundation for its evaluations of hydroxychloriquine and Lopinavir/ritonavir (brand name Kaletra). The evaluations of metformin, ivermectin, and fluvoxamine were funded by Fast Grants. Trial infrastructure is supported by the Rainwater Charitable Foundation.
To find out more about the TOGETHER Trial and the effectiveness of repurposed drugs in the early treatment of COVID-19 among high-risk patients, the Halifax Examiner interviewed Mills, initially over the phone, and then over email.
This interview has been edited for length and clarity.
Linda Pannozzo (LP): Can you explain how this clinical trial works?
Edward Mills (EM): So, we’ve now done five different repurposed drugs plus a placebo. This is a new type of clinical trial. It’s called a platform clinical trial, and it evaluates multiple different interventions at the same time. So [a patient] could only be allocated to one intervention. It’s for early treatment for high-risk patients at risk of being hospitalized with COVID-19, and then the primary endpoint is whether or not they end up getting hospitalized. So, we have already evaluated hydroxychloroquine and the HIV drug called Kaletra. We have also evaluated metformin. We are continuing to evaluate ivermectin — multiple doses — fluvoxamine, which is an antidepressant, and placebo. Then next week, we will begin a new drug called doxasozin, and an injectable drug called Peg-interferon lambda.
LP: And what have you found out so far?
EM: We know what doesn’t work and what doesn’t work is hydroxychloroquine, the HIV drug that I mentioned, Kaletra, and metformin. We know that they don’t work, so we have dropped those arms from our trial. With the other drugs, we don’t yet have confirmation that they do not work. So we are continuing to randomize to those arms.
LP: Can you explain what “randomize” means to a lay audience?
EM: When you enter into a clinical trial, as an investigator, you don’t want to predetermine which intervention a patient should get because you may end up putting your sickest patients onto the strongest drug, for example. What you do instead is you are blind to the allocation that the patient might receive, and then you randomize them — using a random number generator, even as simple as flipping a coin as a random process. So you could flip a coin to determine which arm the patient goes into. Because we’ve got multiple arms, it’s a little bit more complicated, but conceptually it’s the same thing. As an investigator, I don’t influence which drug they are going to receive. So the fact that we have stopped different arms — I mentioned hydroxychloroquine, Kaletra, and metformin, we have stopped all of those — you can infer that those drugs don’t work. We are continuing to evaluate ivermectin, multiple dose, and fluvoxamine, and from that you can infer that we are not yet convinced that these drugs do not work.
It’s a lot of negatives, I realize. What I’m trying to say is I cannot tell you that they do work, but I can also not tell you that they don’t work. So we remain optimistic in evaluating them.
LP: Can you tell me a bit more about why the study came about? I’ve read a couple of articles about the study and how it could have significant implications for low- and middle-income countries.
EM: When we began this trial in June 2020, we did it because we wanted to get the answers the quickest. This is all pre-vaccine availability and of course, in the early days, people were hopeful that some drug like hydroxychloroquine might have a treatment effect that’s useful. There was a lot of optimism for that drug and also the HIV drug. We did that trial very quickly and we determined that they did not work, and this was consistent with other trials that were also being done. In particular, there are the RECOVERY trials by visionary scientists from Oxford University in the UK — they do nice, big convincing trials. The other excellent trial from Oxford is the PRINCIPLE trial. Interestingly, the PRINCIPLE trail is led by Dr. Christopher Butler, who was previously faculty at McMaster University and still holds an appointment. They all do this type of platform trial, which is the multi-arm approach.
So the appeal to repurpose drugs is several fold. The main thing is you already know about their safety profile, so they don’t require the same sort of concerns about safety, because if you take a drug like — let’s just pick Tylenol — if Tylenol worked for COVID, it would be great because we already know all the safety details about it, and you know who should get it and who should not and how much should be prescribed. So the appeal of repurposed drugs is very strong because you know so much about the drugs already, because they were used for whatever their original purpose was.
Whereas when you’re looking at a new drug like the monoclonal antibodies, we know very little about them, we know very little about their safety, whether particular populations are going to react differently to toxic aspects of them, things like that. But with repurposed drugs, we would already have all of that knowledge. 2
The other aspect is most of the repurposed drugs, in fact, all of the repurposed drugs are off patent, which means there should be very, very cheap to acquire, and that’s appealing because who does this disease affect the most? It affects the people who have the least resources, you know, whether that’s poor people in poor countries or even in wealthy countries like Canada, it predominantly affects people with lower resources.
LP: Are you referring to the social determinants of health?
EM: Yes. There are people who tend to live in rooms where there’s a lot of other people or they’re forced to go out to work whether they want to or not. So it’s people who don’t have as much. The wealthy population in Canada never had much to fear about COVID. They just went back to their houses, you know. It’s the people who had to work in the meat plants, for instance, they’re the ones who had to be concerned. And the epidemiology has really played out that this is a disease that predominantly affects the same populations that are affected by other diseases like diabetes, like cardiovascular disease. And they’re all, as you mentioned, social determinants of health. 3
LP: So I know you don’t have the results yet but let’s say hypothetically, that there was something positive that came from the trial and it did show one or more of these treatments to be effective for early treatment of COVID-19 in high-risk patients. I can see how there would be an implication for the low- and middle-income countries, because the drugs are so cheap and access to vaccines is limited. But in a place like Canada, where the vaccine rollout is happening fairly quickly, would there still be a role for these treatments here?
EM: Well, I believe that there is. There’s still lots of new infections occurring here in Canada, and that will continue to be the case. The vaccines are going to be important, but they’re not 100% effective and they’re also not being taken up by everybody. There’s still a lot of people who don’t want to take a vaccine. So we definitely need treatments. And there will be future coronaviruses. So if we found out that any of these drugs have an indication for respiratory illness, it would be fantastic news for Canada and for the world.
LP: Would the variant that’s dominant in Brazil, where the clinical trial is taking place, have any impact on the usefulness of these repurposed drugs in places where that variant is much less dominant?
EM: We won’t know whether variants matter much regarding drugs until multiple trials are conducted. Usually, variants for viruses do not result in differing outcomes for patients — HIV for example — but there is nothing usual about this virus.
LP: In one of the articles I read on these trials, you were quoted saying it could be “a game changer.”
EM: I’m not sure I’ve ever actually used that term. I saw that in The Hamilton Spectator. I don’t recall ever using that term. But it would be. It would be [a game changer] because the only drugs that are shown to be effective at the moment for early treatment of COVID tend to be these monoclonal antibodies … and I’m not convinced those monoclonal antibodies work at all. The results have been so poor … It’s a real struggle to see where that drug would play a role. Whereas if you had a cheap, safe, repurposed drug that you could say, “Well, just pick this up at your pharmacy and use it until you feel better.”
LP: In my research of some of these repurposed drugs I located a review of ivermectin in the May/ June issue of the American Journal of Therapeutics. Have you seen that?
EM: I know of it because the people who published it, overcall the importance of that article.
LP: I was just wondering if you could comment on it, because it concludes that ivermectin should be “globally and systematically deployed in the prevention and treatment of COVID-19.”
EM: I’ll wait for our clinical trial before I would make that recommendation. That particular group who authored that article have a well understood agenda promoting ivermectin, and no amount of evidence is likely to change their mind — whether that be favorable or negative evidence — I don’t think it’s going to change their mind. So one of the problems with the ivermectin topic is that the advocate groups around ivermectin have overcalled the importance of this drug. You can’t go around promoting a drug, calling it a miracle drug that will end the pandemic, when you don’t even have a good clinical trial to support it, and that’s exactly what they did. If indeed this drug has a treatment effect — and I am very optimistic that it will — it will just be one component of the interventions that we need. It’s not going to end the pandemic. And that’s illustrated in India at the moment where Goa did recommend ivermectin, and just over the last few days it was recommended that it actually should stop being used.
LP: Why is that?
EM: They said they’re going to wait for the results from clinical trials like ours. 4
LP: Ivermectin has a long history of being a safe drug, and medical practitioners regularly prescribe drugs “off-label” to treat illnesses, but prescribing ivermectin to treat high-risk COVID patients who have not yet been hospitalized, is, I believe, prohibited in Canada. Given what you know about the drug, what do you see as the danger in it being used off-label to treat early COVID in high-risk patients?
EM: I am not advocating the use of ivermectin until we have good, quality evidence from clinical trials that it is effective.
Here’s the thing: The people who wrote that article [in the American Journal of Therapeutics] claimed that this drug [ivermectin] is a miracle drug that has an effect of about 75% of reducing mortality. That is not far off the effect of a parachute when you jump out of a plane. It would not take much of a clinical trial to know whether that was true or not, and almost every physician would be able to spot really quickly whether there was a drug that miraculously was helping people. But we’re not getting that feedback from physicians and every decent clinical trial that is done on it concludes that there might be a treatment benefit, but it’s not obvious. Whether the drug has an important treatment effect or not, it’s just not going to be as large as what they claim.
LP: So you’re saying — looking at it in a positive way — ivermectin could be one of a group of drugs that would be used, for instance, in treating COVID, but not necessarily just on its own?
EM: That’s correct and almost always in infectious diseases, we require a group of drugs. It’s very rare that one drug is the drug that ends a condition. So if you look at HIV, for example, it’s usually a three-drug cocktail that’s required. Individually, those drugs are almost useless. But you put them together, they’re magic. Hepatitis C, it’s a two-drug combination. Individually, it was really painful for people, but you put them together and you get a cure. That typically is the way that it is with infectious diseases. We’re going to be looking at combinations of drugs.
LP: When do you expect to have your findings finalized, and able to report them?
EM: We’re already reporting on the drugs that we’ve found don’t work, and so those [studies] are published or in the process of being published. We are continuing to randomize: we hit a new milestone today on the patients randomized. So we will do another evaluation on the active drugs probably in the next week or two. And then I think we will not be stopping the trial, even if they’re significant, even if they’re useful, will probably continue randomizing to be absolutely certain. So I suspect we’ve got another month before we reach our full capacity for the two drugs ivermectin and fluvoxamine. So 800 patients on ivermectin, 800 patients on fluvoxamine, 800 patients on placebo. I suspect we’re looking at another month at which time we will have results within a couple of weeks of that.
LP: OK, where do you expect to publish?
EM: In the Journal of the American Medical Association (JAMA). There is a rule of thumb in science — what they call the impact factor of a journal determines how important the journal. So if you publish in The Lancet, it’s got a very high impact factor, it’s usually very important. It’s a sign of good science to publish in a journal with a high impact factor. The one that you mentioned, the American Journal of Therapeutics, it’s not a serious journal.
I know that paper very well because it’s been promoted as being some sort of big deal, but it’s not a big deal. Publishing papers is easy. Doing good science is very challenging. So I don’t have great respect for that. But that group is actually making it much more difficult to make the science be believed because they’re overcalling the importance of what they’re doing. They should just leave the science to the scientists and allow the clinical trials to complete.
The funny thing is I’ve been attacked by that group on social media at times because they can be quite conspiratorial. But now they get the sense that maybe we will give them results that are favorable to them and all of a sudden they think we’re friends, and it’s not an issue of being friends or not. We just want to be able to do the research.
LP: There are people who are taking ivermectin as prophylaxis, and believe it to be a miracle drug, even if those claims are overstated, as you say. They seem to be taking their health into their own hands.
EM: I don’t view the conspiracy theorists as anything other than normal people who are in a very stressful situation, and we have all reacted in weird ways to this pandemic. And I think everybody’s got their different way of viewing it. So I don’t look down on people who have a conspiracy perspective, or whether they believe in masks or don’t believe in masks, or a particular drug. I don’t view these people any differently than I view my scientific colleagues because I’ve seen the scientists make lots of mistakes, too. Even our chief medical officer was telling us not to wear masks back in May last year. So I’m sympathetic to the people.
The evidence on prophylaxis use of ivermectin is not very convincing. But, you know, prophylaxis studies are really tough to do. They’re really, really tough, which is why even the vaccines, you know, they require 40,000 people to be able to determine whether or not there’s a difference between the groups. So they require massive undertakings with huge amounts of funding, and there’s no funding really for ivermectin. So the prophylaxis studies, I don’t think will ever be very useful. But also, I just don’t see the biological mechanism for the prophylaxis role of ivermectin. But I could be wrong. We used to not believe that taking an HIV drug before you get HIV could prevent you from getting HIV. And now we know that actually it does.
I don’t see an antiviral role for ivermectin but I do see a potential anti-inflammatory role. So I can see why it might have a role in treatment, but I don’t see why it might have a role in prophylaxis. But I could be wrong.
I want the public to understand we’re trying to do everything we can to come to believable answers.
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- According to Dr. Nicole Boutilier, VP Medicine with the NSHA, the COVID-19 Therapeutics and Prophylactics Advisory Group was established to provide recommendations to the health system regarding clinical use of antiviral and immunomodulatory agents for treatment of COVID-19 based on evolving evidence and research. “The advisory group is closely tracking antiviral and immunomodulatory therapeutics pursued by the federal government for COVID-19, medications with Health Canada approval for COVID-19, and medications with phase 3 clinical trial data and makes recommendations to the COVID-19 Network who then makes recommendations to Nova Scotia Health’s Clinical Operations Committee and leadership team. Recommendations are reviewed every four weeks and updated as new information and evidence becomes available.” ↩
- For more info on the monoclonal antibodies: https://www.halifaxexaminer.ca/featured/nova-scotia-has-50-doses-of-a-potentially-life-saving-treatment-for-covid-19-so-why-hasnt-it-been-used/ ↩
- For further reading on the social determinants of health: https://www.halifaxexaminer.ca/featured/double-exposure/ ↩
- According to The Times of India, in early May 2021, Goa’s health minister Vishwajit Rane announced that the State would give those older than 18 years of age ivermectin as a prophylactic against severe COVID-19. Rane said the decision was based on studies in the US and UK. The next day, the chief scientist for the World Health Organization, Soumya Swaminathan recommended against its use to treat COVID patients, except within clinical trials. ↩