I’ve been writing a lot about the unjustified and premature hype over hydroxychloroquine, an anti-malarial drug with mild immunosuppressive activity that is also used to treat rheumatoid arthritis and other autoimmune diseases and how the drug probably doesn’t work against COVID-19, despite its being hyped by President Trump and his sycophants, toadies, and lackeys on Fox News, Dr. Mehmet Oz, Dr. Phil, Dr. Didier Raoult, and a bevy of irresponsible fame seeking doctors who have no idea how to do a proper clinical study. There are, however, other drugs being hyped out there, drugs that might actually have a better chance of turning out to be effective treatments for COVID-19. Chief among these is remdesivir, the experimental antiviral drug being tested by Gilead Sciences. Remdesivir is an adenosine (a nucleotide) analog that inhibits viral RNA polymerases. It is incorporated into RNA made by the virus, causing the premature termination of the RNA molecule, thus interfering with viral replication. The drug was originally developed to treat Ebola and Marburg but was ultimately found to be ineffective against these viruses. Because it inhibits the replication of a number of RNA viruses, it was only natural that it would be considered as a possible treatment for COVID-19, and Gilead has been relentlessly promoting it as such as the company has been working to carry out clinical trials.
What prompted me to write about remdesivir were headlines like Dr. Anthony Fauci says Gilead’s remdesivir will set a new ‘standard of care’ for coronavirus treatment that started popping up on Wednesday afternoon:
White House health advisor Dr. Anthony Fauci said Wednesday that data from a coronavirus drug trial testing Gilead Sciences’ antiviral drug remdesivir showed “quite good news” and sets a new standard of care for Covid-19 patients.
Speaking to reporters from the White House, Fauci said he was told data from the trial showed a “clear-cut positive effect in diminishing time to recover.”
Fauci said the median time of recovery for patients taking the drug was 11 days, compared with 15 days in the placebo group. He said the mortality benefit of remdesivir “has not yet reached statistical significance.”
The results suggested a survival benefit, with a mortality rate of 8% for the group receiving remdesivir versus 11.6% for the placebo group, according to a statement from the National Institutes of Health released later Wednesday.
“This will be the standard of care,” Fauci, director of the National Institute of Allergy and Infectious Diseases, added. “When you know a drug works, you have to let people in the placebo group know so they can take it.”
My skeptical antennae started twitching immediately, because on the same day a study from China was published in The Lancet that was far less impressive. In fact, it was a negative trial. What also got my skeptical antennae all aflutter twitching away was how the results of the remdesivir trial were announced. Normally, when a study is announced to the press, it’s upon publication of the paper, and the press release is issued either the same day or the evening before publication. As of last night, as I wrote this, however, the actual paper reporting the results of the clinical trial had not yet been published. As I perused Twitter on Wednesday, I found even more reasons for skepticism.
So, before I get to the study touted by Dr. Fauci, let’s review some history.
Remdesivir: The early days versus COVID-19 (like, you know, three weeks ago)
The first data published on remdesivir was a single-arm uncontrolled trial that somehow got published three weeks ago in The New England Journal of Medicine. This was peak COVID-19 publishing, when an uncontrolled case series of patients with severe COVID-19 treated with remdesivir under compassionate was published in a super high impact journal like NEJM and made headlines as a result. Be that as it may, the case series examined 61 patients with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing room air or who were receiving oxygen support. They received a 10-day course of remdesivir, consisting of 200 mg given intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. (Remdesivir is an intravenous drug.) The authors reported clinical improvement in 68% of evaluable patients:
Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.
The case series also did not collect viral load data to confirm potential antiviral activity in humans or any association between declines in viral load and clinical improvement. Basically, when you get right down to it, this study was not really much better than Didier Raoult’s crappy study of his hydroxychloroquine/azithromycin combination, but that didn’t stop the authors from concluding that comparisons with contemporaneous cohorts “suggest that remdesivir may have clinical benefit in patients with severe Covid-19.” In reality, like Raoult’s trials, this trial said nothing about the efficacy of remdesivir against COVID-19 other than that the drug could be given to COVID-19 patients with a reasonable safety profile.
Less than week later, as related by Derek Lowe, came news that two clinical trials of remdesivir in China, one for severe disease and one for moderate disease had been suspended. (They still are.) Lowe noted that both trials had the notice: “The epidemic of COVID-19 has been controlled well at present, no eligible patients can be recruited.” The apparent explanation was “the stringent inclusion criteria for the trials – apparently patients had to have no previous therapy with any other experimental agent to enroll, and that eliminates a lot of people.” Around the same time, Adam Feuerstein and Matthew Herper published a story in STAT, Early peek at data on Gilead coronavirus drug suggests patients are responding to treatment:
The University of Chicago Medicine recruited 125 people with Covid-19 into Gilead’s two Phase 3 clinical trials. Of those people, 113 had severe disease. All the patients have been treated with daily infusions of remdesivir.
“The best news is that most of our patients have already been discharged, which is great. We’ve only had two patients perish,” said Kathleen Mullane, the University of Chicago infectious disease specialist overseeing the remdesivir studies for the hospital.
Her comments were made this week during a video discussion about the trial results with other University of Chicago faculty members. The discussion was recorded and STAT obtained a copy of the video.
Derek Lowe discussed this story in depth, and I largely agree with him that the leak of the video to STAT was a serious breach of clinical trial ethics and protocol. (I’m not alone in suspecting that it was almost certainly intentional to jack up Gilead’s stock price, a result that was achieved.) Lowe also noted:
But now that it’s out there, let’s talk about what’s in the leak. Gilead stock jumped like a spawning salmon in after-market trading on this, and one of the reasons was that that 113 of the 125 patients were classed as having “severe disease”. People ran with the idea that these must have been people on ventilators who were walking out of the hospital, but that is not the case. As AndyBiotech pointed out on Twitter, all you had to do was read the trial’s exclusion criteria: patients were not even admitted into the trial if they were on mechanical ventilation. Some will have moved on to ventilation during the trial, but we don’t know how many (the trial protocol has these in a separate group).
Note also that this trial is open-label; both doctors and patients know who is getting what, and note the really key point: there is no control arm. This is one of the trials mentioned in this post on small-molecule therapies as being the most likely to read out first, but it’s always been clear that the tradeoff for that speed is rigor. The observational paper that was published on remdesivir in the NEJM had no controls either, of course, and that made it hard to interpret. Scratch that, it made it impossible to interpret. It will likely be the same with this trial – the comparison is between a five-day course of remdesivir and a ten-day course, and the primary endpoint is the odds ratio for improvement between the two groups.
Again, these data, such as they are, are no more useful than Didier Raoult’s data on hydroxychloroquine and azithromycin to treat COVID-19, but this brings us to the Chinese trial published in The Lancet on Wednesday.
The Chinese randomized clinical trial
The Chinese trial published two days ago is the first randomized, double-blind, placebo-controlled clinical trial of remdesivir to treat COVID-19, but it was also one of the studies halted. Eligible patients were adults admitted to the hospital with laboratory-confirmed SARS-CoV-2 whose symptoms had lasted less than 12 days before enrollment and who had an oxygen saturation on room air of 94% or less or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less (another measure of hypoxia), and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir at the same dose as the NIH trial touted by Dr. Fauci or the same volume of placebo infusions for 10 days and were permitted concomitant use of lopinavir–ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined at the time from randomization to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. An intention-to-treat analysis was carried out.
Basically, this was a negative trial. Of the 255 patients screened, 237 met the eligibility criteria, and 158 were assigned to the remdesivir group, with 79 assigned to placebo control. Unfortunately, remdesivir treatment was not associated with a shorter time to clinical improvement, and mortality was not different between the two groups. Subgroup analysis looking for hypotheses found that there was a trend towards a shorter duration of symptoms (not statistically significant) in patients treated with remdesivir who had had symptoms for less than ten days. Most disappointingly, there was no detectable difference in viral load between the remdesivir groups and the placebo controls. Again, basically this was a negative study with only the barest hint that remdesivir might—I repeat, might—work if administered earlier in the course of COVID-19. That’s some pretty thin gruel.
Which brings us to the NIH trial of remdesivir touted by Anthony Fauci.
The NIH press release for its remdesivir trial.
The results of the NIH remdesivir trial can, unfortunately, only be gleaned from the press release and news stories so far:
For the first time, a major study suggests that an experimental drug works against the new coronavirus, and U.S. government officials said Wednesday that they would work to make it available to appropriate patients as quickly as possible.
In a study of 1,063 patients sick enough to be hospitalized, Gilead Sciences’s remdesivir shortened the time to recovery by 31% — 11 days on average versus 15 days for those just given usual care, officials said. The drug also might be reducing deaths, although that’s not certain from the partial results revealed so far.
“What it has proven is that a drug can block this virus,” the National Institutes of Health’s Dr. Anthony Fauci said.
“This will be the standard of care,” and any other potential treatments will now have to be tested against or in combination with remdesivir, he said.
Here is the press release, posted to the National Institute of Allergy and Infectious Diseases website:
Hospitalized patients with advanced COVID-19 and lung involvement who received remdesivir recovered faster than similar patients who received placebo, according to a preliminary data analysis from a randomized, controlled trial involving 1063 patients, which began on February 21. The trial (known as the Adaptive COVID-19 Treatment Trial, or ACTT), sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is the first clinical trial launched in the United States to evaluate an experimental treatment for COVID-19.
An independent data and safety monitoring board (DSMB) overseeing the trial met on April 27 to review data and shared their interim analysis with the study team. Based upon their review of the data, they noted that remdesivir was better than placebo from the perspective of the primary endpoint, time to recovery, a metric often used in influenza trials. Recovery in this study was defined as being well enough for hospital discharge or returning to normal activity level.
Preliminary results indicate that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (p<0.001). Specifically, the median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059).
More detailed information about the trial results, including more comprehensive data, will be available in a forthcoming report. As part of the U.S. Food and Drug Administration’s commitment to expediting the development and availability of potential COVID-19 treatments, the agency has been engaged in sustained and ongoing discussions with Gilead Sciences regarding making remdesivir available to patients as quickly as possible, as appropriate. The trial closed to new enrollments on April 19. NIAID will also provide an update on the plans for the ACTT trial moving forward. This trial was an adaptive trial designed to incorporate additional investigative treatments.
As you can see, the difference in mortality was not statistically significantly different, although that could just be because of inadequate numbers. It’s also very important to note the part about the adaptive trial design of this trial, which puts Dr. Fauci’s comment about how remdesivir will become the “standard of care” going forward into the proper context. In this particular trial, multiple different drugs can be compared to placebo or standard of care. The idea is that, if a signal of efficacy is found with one drug, that drug becomes “standard of care” and the trial is adapted to study how adding other experimental drugs compares to the “standard of care.” So what Dr. Fauci meant was that, based on the finding, going forward remdesivir will become the “standard of care” arm for the trial and the experimental arm will become remdesivir plus another experimental therapeutic. However, given that the FDA is on the verge of issuing an emergency use authorization for remdesivir to treat COVID-19, it looks as though remdesivir will become standard-of-care in general soon.
But back to the results. Derek Lowe observed:
… it’s worth noting that had there been “clear and substantial evidence of a treatment difference” during the trial that the DSMB was to have halted the study at that point. We can infer that nothing rose to that level, then: we have a difference, but not substantial enough to have ended the trial prematurely.
It’s also worth noting some things posted on Twitter about the trial. For instance, Waller Gellad noted:
It’s very odd that the primary endpoint was changed:
This long Twitter thread explains:
I’ll summarize, so that you don’t have to scroll through a Twitter thread if you don’t want to. As James Heathers and Waller Gellad noted, the original primary outcome of the trial when it was registered on March 20. The original primary endpoint of the trial was an 8-point severity scale (death, on ventilator, hospitalized with oxygen, all the way down to discharged with no limits on activity) but was changed to time to recovery. There’s still a similar scale for the secondary endpoints, but no numbers for that were reported. (Any bets on whether the results are negative?) This change was apparently made on or around April 16.
Gellad also notes:
It does look very fishy to me. Endpoint or outcome switching, particularly late in a clinical trial is a huge red flag. Don’t get me wrong. There can be legitimate scientific reasons to switch primary endpoints of a trial. as James Heathers puts it:
There are also other reasons to question this trial, including how no confidence intervals were reported, that not even an abstract was published, just a press release with, as Heathers put it, “two results in four lines”:
Basically, if you have two “good” results and twenty “bad” or uninterpretable results, what do you do? What are you going to tell people? The two “good” results, of course!
Gary Schwitzer has a nice summary of the negative reactions to the trial and how it was announced.
The bottom line
I remain very suspicious that the NIH study was announced the same day that a negative study out of China of remdesivir was published. It just seems too…convenient. Maybe I’m being overly suspicious. Maybe I’m too suspicious. Maybe I’m falling prey to conspiracy mongering. However, in the Trump era, when the Trump administration has politicized previously (mostly) apolitical government agencies as never before, it’s hard not to wonder.
Adding to my suspicion is the fact that the study was reported in a press release, rather than being published, which makes me wonder if the press release was written to counter the negative study from China that would certainly have tanked Gilead’s stock prices. Yes, I know that the press release reported that this decis, apparently the announcement was decided upon after April 27 meeting of the data and safety monitoring board overseeing this trial, but the outcome switching so late in the trial makes me very suspicious. Yes, the explanation, which should have been in the press release, along with an acknowledgment that the primary outcome/endpoint had been changed, but wasn’t is not unreasonable:
Then there was this news report in which Fauci claimed that concerns about leaks fueled the announcement:
He expressed concern that leaks of partial information would lead to confusion. Since the White House was not planning a daily virus briefing, Fauci said he was invited to release the news at a news conference with Louisiana Gov. John Bel Edwards(D). “It was purely driven by ethical concerns,” Fauci told Reuters in a telephone interview.
“I would love to wait to present it at a scientific meeting, but it’s just not in the cards when you have a situation where the ethical concern about getting the drug to people on placebo dominates the conversation.”
An independent data safety and monitoring board, which had looked at the preliminary results of the NIAID trial, determined it had met its primary goal of reducing hospital stays.
On Tuesday evening, that information was conveyed in a conference call to scientists studying the drug globally.
“There are literally dozens and dozens of investigators around the world,” Fauci said. “People were starting to leak it.” But he did not give details of where the unreported data was being shared.
I smell bullshit here. What probably really happened is that he was under enormous pressure to release the results. It was also…unwise…to discuss the results with so many scientists until the manuscript reporting the results of the trial had at least been submitted for publication. I agree with the scientists who had “expected it [the trial data] to be presented simultaneously in a detailed news release, a briefing at a medical meeting or in a scientific journal, allowing researchers to review the data.” I also agree with Dr. Eric Topol, referring to the Chinese RCT and this one:
“That’s the only thing I’ll hang my hat on, and that was negative,” said Dr. Eric Topol, director and founder of the Scripps Research Translational Institute in La Jolla, California.
He was unimpressed by remdesivir’s modest benefit.
“It was expected to be a whopping effect,” Topol added. “It clearly does not have that.”
Indeed, given that the pre-test probability of remdesivir having a significant effect was low, meaning that this trial is probably just noise:
Indeed, I’m not only unimpressed with the modest benefit reported, I question whether there really was any benefit at all, particularly in light of the Chinese trial, which found zero difference in viral load in the remdesivir group.
The whole thing looks damned fishy, and we can’t judge the study until it’s actually published. Meanwhile, whatever the true reasons for releasing the study results this way, mission accomplished. The negative effect of the Chinese study on Gilead’s stock price was successfully countered and remdesivir becomes a de facto standard of care for patients hospitalized with COVID-19. Worse, no further trials of remdesivir versus placebo will be possible, because it’s been declared that remdesivir “works” against COVID-19 and is the new standard of care! As Mark Hoofnagle put it in a great Twitter thread, that echoes my thoughts:
It’s worse than that. If remdesivir is now the “standard of care” for hospitalized COVID-19 patients, it now becomes unethical to randomize them to a placebo group testing ANY new drug for COVID-19. Trials will now have to compare remdesivir alone to remdesivir plus experimental drug. We’ll probably never know now for sure if remdesivir is truly effective against COVID-19.
But Gilead will make billions and billions of dollars.