A Quick Take on STAT’s Remdesivir April 16 Reporting

Last week, STAT News reported that a clinical trial treating severe COVID-19 patients with Gilead Sciences’ antiviral medicine, remdesivir, at University of Chicago Medicine was performing well. In the article. Dr. Kathleen Mullane, the infectious disease physician running the trial, said, “The best news is that most of our patients have already been discharged, which is great. We’ve only had two patients perish.”

“It’s always hard,” she said, “because a severe trial doesn’t include a placebo group or comparison…but certainly, when we start the drug, we see fever curves falling. Fever is now not a requirement for people to go on the trial. When patients do come in with high fevers, they reduce quite quickly. We’ve seen people come off ventilators the day after starting therapy…overall, our patients have done really well.”

“Most of our patients are severe, and most of them are leaving at six days,” Dr. Mullane concluded. “So that tells us duration of therapy doesn’t have to be 10 days. We have very few that went out to 10 days, maybe three.”

The reporting also included an anecdote about a patient who went on therapy and was quoted as saying, “Remdesivir was a miracle.”

To learn more, GLG sat down with Dr. Davidson Hamer, Professor of Global Health and Medicine at the Boston University Schools of Public Health and Medicine and a faculty member in the National Emerging Infectious Diseases Laboratory.

What is your immediate response to this news report (from April 16)?

In my opinion, this is a bit unusual because in an early trial, there usually wouldn’t be any reporting until it’s done. But it does sound encouraging from the data described there.

That said, I think you have to take it with a grain of salt. This is not a controlled trial. It’s really a trial comparing two different durations of therapy, 5 days versus 10 days. It’s hard in the absence of a control or a standard-of-care group to say that something’s working.

Let’s start with the trial’s design. It is the severe trial that Gilead is running? How is it defining “severe”? Can you walk us through this?

It’s a complicated design. Structurally, the trial has two arms – it’s 5 days versus 10 days of remdesivir. Then it has what looks like an extension to that, an additional 5 or 10 days for participants who need more time on treatment, which is for those who started out with a 5-day course.

The key inclusion criteria is that these are not mechanically ventilated patients. But there’s the potential for patients that end up needing mechanical ventilation to have an additional 10-day course. The eligibility criteria, at least for the initial part, are people over 12 years old with SARS-CoV-2 confirmed by PCR within four days before randomization and, notably, oxygen saturation less than or equal to 94%.

Further, patients cannot be participating in any other clinical trial, can’t have multi-organ failure, or can’t have had any other antiviral drugs that might have activity against SARS-CoV-2 within 24 hours prior to study drug dosing.

This is important because a lot of hospitals across the U.S. and the globe are trying hydroxychloroquine, sometimes with azithromycin. In addition, they’re trying other immunomodulatory strategies. To test this in a clean manner, it’s important for a patient to not have another antiviral drug in their system.

It’s a little tricky with a drug like hydroxychloroquine, which has a fairly long half-life. If you’ve taken it for three or four days, it’s not going to be out of your system 24 hours later. But that’s just a minor issue. Finally, those with renal insufficiency and evidence of fairly severe hepatic dysfunction are excluded. This trial includes a sick group, but I would say not quite critically ill.

The goal is to look at the odds of improvement by comparing the two treatment groups. And they’re likely doing this daily to track the time frame for improvement, with major outcomes being mortality, hospitalization with the need for invasive mechanical ventilation, or extra-corporeal membrane oxygenation (ECMO) or other high-flow oxygen devices.

The secondary outcome is safety. Are there any treatment-emergent adverse events associated with the treatment? I’d define this as a true compassionate use trial without a control comparing two different durations for moderately severe COVID-19. And based on the STAT reporting leaked from the hospital in Chicago, it does sound promising. But again, I think we need more follow-up, more data from other sites, and to learn more about its activity in this context.

The STAT article reported a rapid drop in fever and a quick removal from mechanical ventilation in many cases. Is it reasonable to expect that someone on a drug like this could be weaned from ventilatory support within a day or having their fever drop that quickly when they’re this ill?

My short answer? No. If this is an antiviral drug and if it’s leading to a reduction in viral load and the concentration of virus, it should take several days to have an effect. Theoretically, it might make more sense to be using this early in the course of the illness to try and prevent the cytokine storm that can develop and lead to rapid respiratory deterioration and the need for ventilation.

It’s surprising that it seemed to have such a rapid onset of action. You’d almost expect that with something that interferes with cytokine activity or has some other mechanism of action. So that makes me a little skeptical about these results.

Can you comment on the assertion that the therapy would not need to be 10 days? Are there other antiviral treatments that could serve as some sort of reasonably logical benchmark comparing to that?

 I think it’s plausible. Again, this is a severely ill group with a disease that’s relatively novel for us in terms of treatment with antiviral agents. If you look at influenza, the typical treatments are only five to seven days. A full 10 days may not be necessary. A short course may be feasible.

To be sure, it would help to have more data. But this is a very sick group, so I’m skeptical still about these results. It could be that a short course – like five days – in patients with earlier disease may make a difference in their trajectory and what happens next. If it can reduce the viral load sufficiently and allow their immune systems to really kick in, then it might prevent complications from developing.

In those who are severely ill like this, there’s a lot of damage from the imprudent inflammatory cytokine response, and maybe it’s less driven by the virus directly, although the virus is initially responsible for it.

You mentioned that this is not a placebo-controlled trial. When we do see data from placebo-controlled trials, what would jump off the page at you when looking at the data and make you say, “Wow. This is incredible. This drug is working really well?” Or even if it does show efficacy, what would disappoint you?

 A significant difference in clinical outcome. If it’s starting out with patients who are not ventilated but have high toxemia – they have low oxygen concentrations in their blood – then if the treatment changes the progression and prevents a larger proportion of patients from needing ICU admission and mechanical ventilation or other types of more intensive oxygen support, then that would be a big win.

 If it doesn’t do that but there’s some small changes, let’s say, duration of hospitalization, it would be less exciting as an option. The other big one is if they were to show a mortality difference between this intervention and placebo. That would be big news. I’m skeptical that that will happen, but you never know. I’d say preventing progression to mechanical ventilation and preventing mortality would be two very meaningful clinical outcomes.

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About Dr. Davidson Hamer, MD

Dr. Davidson Hamer is a Professor of Global Health and Medicine at the Boston University Schools of Public Health and Medicine, a faculty member in the National Emerging Infectious Diseases Laboratory, and an Adjunct Professor of Nutrition at the Tufts University Friedman School of Nutrition Science and Policy. Dr. Hamer is an infectious disease specialist and medical epidemiologist with particular interests in emerging diseases, tropical medicine, travel medicine, antimicrobial resistance, and maternal, newborn, and child health (MNCH).

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This article is adapted from the April 17, 2020, GLG teleconference “Remdesivir Potentially Working, Reports STAT News: COVID-19 Epidemiological Outlook, Monitoring, and Control Measure.” If you would like access to this teleconference or would like to speak with Dr. Hamer or any of our more than 700,000 experts, contact us.

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