Medical News Today interviewed Dr. Catherine Oldenburg, co-principal investigator in a brand new human trial examining the potential effectiveness of azithromycin, a common antibiotic, in treating milder cases of COVID-19, which the new coronavirus causes.
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The FDA have removed the Emergency Use Authorization (EUA) for hydroxychloroquine and chloroquine for the treatment of COVID-19. Based on a review of the latest research, the FDA determined that these drugs are not likely to be an effective treatment for COVID-19 and that the risks of using them for this purpose might outweigh any benefits.
Recently, a team of investigators affiliated with the Francis I. Proctor Foundation at the University of California, San Francisco (UCSF), decided to investigate the potential of a common antibiotic — azithromycin — in treating mild-to-moderate cases of COVID-19 that do not require hospitalization.
The trial — called Azithromycin for COVID-19 Treatment, Investigating Outpatients Nationwide, or ACTION for short — will involve human participants, and the researchers started recruiting on May 26, 2020.
To learn more about the trial, and understand why the researchers chose to study azithromycin, despite specialists typically advising against antibiotics in the treatment of COVID-19, Medical News Today spoke to one of the trial’s principal investigators, Catherine Oldenburg, Sc.D., an infectious disease epidemiologist.
We have lightly edited the interview transcript for clarity.
MNT: What is the ACTION trial? Can you tell us a little about its premise and how it will work?
Catherine Oldenburg: The ACTION trial is a nationwide trial in the United States that is designed to evaluate the efficacy of a single dose of azithromycin compared to placebo for [the] prevention of hospitalization in COVID-19 patients who are not currently hospitalized, so patients who have […] anywhere from asymptomatic to moderate disease that doesn’t require hospitalization, and the trial is designed to be flexible and scalable.
It will be open to patients nationwide in the U.S.; it’s conducted remotely out of our trial coordinating center at UCSF.
So, patients can contact the study team from anywhere in the U.S. and be screened remotely, go through all [the initial] processes, and then we ship them [the] study drug and sample collection kits.
MNT: How did you and your team zero in on azithromycin as a potential treatment for COVID-19?
Catherine Oldenburg: It’s a great question. I think that […] it’s absolutely true, the mantra that […] antibiotics don’t treat viral infections. And so, it’s a little bit counterintuitive [to use azithromycin in the treatment of COVID-19, which is the result of a viral infection].
My team has been working with azithromycin and studying [it] for a number of indications for decades. Proctor [The Francis I. Proctor Foundation at UCSF], in general, has been working with azithromycin for trachoma control, which is an infection of the eye, [for] the last 20 years.
And so, in terms of trials [for] azithromycin, that’s something that we do a lot of. I have something like eight trials going on right now with azithromycin, most of which are for trachoma, or for childhood mortality in Sub-Saharan Africa, where there’s a large burden of bacterial disease that’s [an existing issue].
But one of the interesting things about azithromycin is that it has really strong immunomodulatory effects, so it has these kind of nondirect effects on the immune system. That means it’s an interesting candidate in terms of what it does to the immune system.
And then […], I don’t remember the exact date, but there was a study out that kind of created a lot of hype around azithromycin in combination with hydroxychloroquine, and that’s sort of when we got interested, [thinking]: If there’s any indication that perhaps azithromycin has an effect against COVID-19, or against SARS-CoV-2, perhaps that’s something that we should be taking a look at because our team really has a lot of expertise in terms of azithromycin trials, specifically, and in conducting large trials.
Azithromycin is very safe; it’s prescribed all the time for all kinds of things; it’s something that people are very familiar with in a Z pack in the U.S. It seemed like a good candidate for outpatients — if it had an effect — because of its safety profile. And we decided to look at it independently of hydroxychloroquine, given concerns about [the latter’s] safety.
There are a lot of other trials going on with hydroxychloroquine, and we didn’t really feel like we needed to get involved in that because that was outside of our area of expertise.[…] That [is why] we’re looking at azithromycin by itself.
And, we thought, given the safety profile of azithromycin, that this [drug] could be potentially valuable [in treating COVID-19], and to have that kind of evidence would be really useful.
MNT: Can you tell us more about the mechanisms through which azithromycin produces immunomodulatory effects?
In terms of [the] mechanism, there [are] anti-inflammatory type effects with azithromycin. I’m an epidemiologist; I’m not a biochemist, [so] I can’t get into the biology of it so much. But I do think that nobody really knows what the mechanism is. Like, for example, with Zika, and in vitro studies with SARS-CoV-2, as well, nobody really knows what the mechanism is.
So, you know, it could be that there’s a direct antiviral effect. If I had to guess, I would say it’s probably unlikely, but [it] also could be that you’re reducing [the need for a more complex] treatment [by administering azithromycin].
A course of azithromycin or a dose of azithromycin could reduce other bacterial loads in patients who are presenting with both [COVID-19] and a bacterial pneumonia.
If you treat the bacterial pneumonia, [it] can free up the immune system to fight COVID-19, or it could be this immunomodulatory and anti-inflammatory response, which brings down inflammatory markers, [and] in general, allows the body to more efficiently fight the virus.
ACTION is not really designed to look at mechanisms. Specifically, it’s really just designed to look at clinical and virological outcomes in patients.
MNT: Lately, there has been a lot of talk about the issue of antibiotic resistance. Do you have any concerns in this respect, seeing that the trial is for an antibiotic?
Catherine Oldenburg: Yes, definitely. You know, I think that studies have shown, trials have shown that a course of azithromycin, a course of antibiotics, in general, does select for resistance in multiple body sources, so, in the intestines and in the nasopharynx (the back of the nose). It is something that you definitely see: Short term increases in isolation of resistance, following a course of antibiotics, and for the long term, the effects of that are unknown.
I think, in terms of doing a trial of azithromycin, the resistance point is really key for doing a trial because if we know that azithromycin does not work for COVID-19, that means that providers won’t be prescribing [it] for COVID-19.
But if there’s this sort of general feeling — which I think there is right now — that’s kind of, well, maybe it might help, maybe it doesn’t hurt, then we might actually, paradoxically, see more prescribing of azithromycin.
So, from my perspective, I’d like to know whether or not it does help. And if it does help then perhaps the trade-off of the resistance is a more warranted one versus if it does not help — then, you know, we have clear evidence that we don’t need to be prescribing azithromycin for outpatients with COVID-19.
MNT: How has the pandemic impacted the practical aspects of getting this trial underway?
Catherine Oldenburg: It’s interesting how many things we took for granted before COVID-19 — you know, [like the] moving of supplies. And even just when we were designing the study, and we were trying to get a hold of swabs.
So, we’re sending patients a self-swab collection kit — it’s an opt-in, if they want to collect swabs, they can collect their own nasal swabs — and just finding a supplier for swabs was really very, very challenging.
Fortunately, we do a lot of sample collection as part of our normal trials, and we have a stock of supplies in our lab [already], but not study drugs.
Editor’s note: When MNT conducted this interview, the trial had not yet started, largely due to delays in receiving the study drug from the overseas provider.
Catherine Oldenburg: I think the first [challenge that we encountered] is just kind of the pace of it [the pandemic]. I mean, there’s this urgent need. We have this horrible infection that’s affecting so many people all over the world, and we have no good treatment for it.
I know that there’s some signal from at least one press release about remdesivir for hospitalized patients, but, you know, in terms of preventing patients from having to be hospitalized in the first place, there’s just really no good evidence. And so, there’s really this prerogative to look at what we call repurposed drugs, the drugs that have indication for something else, and to look at it as quickly as possible.
And, for example, I keep hearing people say things like, “in the U.S. we’ve had 1.3 million cases of COVID-19.” In an ideal world, every single one of those patients could contribute to a clinical trial, because then we would be moving along the evidence.
In the scheme of things, we think we need about 2,000 patients in our trial to arrive at an answer for whether or not azithromycin works, and with 1.3 million infections that, hopefully, should be possible.
So, there’s this kind of pressure, this time pressure that you don’t normally see. Normally, to get a trial like this started, it would take a year, maybe, of planning and of getting regulatory approvals and getting ethical approvals and all that stuff.
And, you know, under this situation we went from first concept of trial idea to all of our approvals being in place in less than 6 weeks, which is […] just really, really, really fast paced. That was exciting, and sometimes a little overwhelming.
So, I think that’s the first thing, that the timelines are sort of crunched, and […] I think there’s also this [other] element: […] for the work that I do normally, we’re talking about diseases where the epidemiology is fairly well described. It may be changing over time, but it’s changing really slowly.
I work mostly in trachoma and child mortality. Both of those are declining over time [in terms of the epidemiology], but they’re declining really, really, really slowly, so I can design a trial that’s going to be implemented in a year and have a pretty good idea of what the epidemiology in a year is going to look like.
It’s completely different with COVID-19. I don’t know what the epidemiology is going to look like next week.
And, it’s so complicated with, you know, just the kind of social and political dimensions of it. So, when we’re thinking about trial design, we don’t have good epidemiology to make assumptions, for example, for sample size calculations. We don’t know exactly what the timeline of the infection is going to look like.
When we first started designing this trial, I don’t think any of us were thinking [about] second wave infections in the fall, that sort of thing. We were thinking “we need to get this done in the spring, we’re going to get it done quickly in a couple [of] months, and that’s going to be over.” And now we’re thinking, “well, maybe this is going to last longer.”
And then, [there are] the supply chain issues, just [the] logistics of getting a trial started when you have to move, for example, study drug products across the world. Normally, that’s something that takes some logistics and planning but doesn’t have [to reckon with] this global economic shutdown that we’ve been seeing, in terms of flights [being grounded], in terms of people moving.
Normally, that just wouldn’t be a consideration like this. So I think it’s [multiple] dimensions affecting this particular trial.
MNT: Finally, how can people who may be interested in joining the ACTION trial enrol in it?
Catherine Oldenburg: [Prospective] participants [who] think they might qualify for the trial can go fill out [the] screening form [on the ACTION trial website], which initiates contact with our study staff, and then someone on our study team would get back to that person via phone or [other means of contact].
Disclaimer: People should always consult with their doctor or other healthcare professionals before taking any medication.
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