As the presidential race looms large, Republicans are also in a fierce contest to retain control of the Senate
Several readers have written to inform us about Richard Bartlett, a Texas doctor and onetime congressional candidate who says he has discovered a “silver bullet” for COVID-19. His proposed cure? Inhaled steroids.
This would be world-changing news, probably deserving a Nobel Prize, if true. It would save thousands of lives, end the economic and social upheaval caused by preventive measures, and save billions of dollars on hospital treatments.
As the ancient Spartans famously said: “If.”
I can’t say with certainty Dr. Bartlett hasn’t discovered a cure, for the same reason he shouldn’t imply that he has: What he currently has is a hypothesis, one whose evidence is as yet too limited to conclude that the treatment works at all, much less that it works in most or all COVID-19 patients. We simply don’t know. So how could we find out whether it’s a blockbuster—or a bust?
Back in March, we discussed a statistic called the “number needed to treat” (NNT). The NNT is the number of patients we’d need to treat in order to expect a medicine to have the desired effect in one patient. For a perfect treatment that benefits every patient who receives it, the NNT is 1. For many common prescriptions, though—statins for prevention of a heart attack, for instance—the NNT is more in the range of 20 to 100. You’d need to treat 20 to 100 patients in order to benefit just one.
Many medical conditions and illnesses go away by themselves. Given the relatively high NNT of many treatments, it’s often hard for researchers to tease out whether a new treatment is improving patient outcomes, or whether those patients would have fared equally well without the treatment.
This timeless source of job security for research statisticians brings us back to Dr. Bartlett and his series of patients. According to CBS7, Bartlett says he’s treated “dozens” of COVID-19 patients and all have survived. Since most patients with COVID-19 do survive, it raises the question: Did his patients benefit from the steroids, or were they patients who would have survived anyway?
Answers are on the way: Oxford and the Queensland University of Technology are already investigating this idea with their STOIC (Steroids in COVID-19) clinical trial. Queensland University of Technology elaborates on its origins: Two researchers “had noticed early on in the pandemic that people with asthma and the chronic lung disease COPD were under-represented in the numbers of seriously ill COVID-19 patients.” This struck them as unusual, since you’d normally expect patients with sick lungs not to have an advantage against respiratory viruses. That made them wonder whether those patients’ inhaled steroid treatments might be what was helping them.
In light of the recent discovery that another corticosteroid can help in severe cases of COVID-19—but not in less severe disease—I’m very curious to learn what the STOIC trial will reveal. STOIC aims to reach a conclusion by September.
In the meantime, let’s not—pardon the pun—jump the gun in our search for a silver bullet.
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In the race to defeat the coronavirus, the finish line is the mass production of a safe, effective vaccine.
Just as Jonas Salk’s vaccine helped transform polio from feared menace to historical curiosity in most countries, a good vaccine against today’s coronavirus would restore the world’s confidence, both socially (potlucks! concerts! sports!) and economically. So where does the vaccine race stand now?
The U.S. federal government’s unprecedented Operation Warp Speed project involves building factories to produce yet-unproven vaccines. That will allow the vaccines to come to market quickly if studies bear out their effectiveness. The Food and Drug Administration is speeding up the normal multiyear approval process with a “rolling review” that evaluates safety data as it comes in. (Here’s an excellent graphical summary.) The FDA has decided that, to be approved, a vaccine must make people 50 percent less likely to contract coronavirus or must reduce symptoms by 50 percent.
The nearly 150 coronavirus vaccine research projects—as of the World Health Organization’s latest count—have the same goal, but differ in their methods: Should a vaccine use an inactivated strain of the now-circulating SARS-CoV-2? Or should it use another, less dangerous virus, genetically modified to appear similar enough to the coronavirus that it will fool the person’s immune system? What if the vaccine doesn’t use a virus at all, but rather a protein the virus makes, or the messenger RNA (“mRNA”) that encodes a protein?
The World Health Organization (WHO) lists 19 vaccine candidates as having started human clinical trials as of July 6—with 130 more in pre-clinical animal studies. (Clinical research typically begins in phase 1, involving dozens of participants, and progresses to phase 3, involving thousands.)
- WHO lists only one vaccine candidate as having started phase 3 trials: ChAdOx1-S vaccine, a modified adenovirus vector from the University of Oxford and AstraZeneca. Sinovac’s inactivated virus vaccine is also about to start recruiting patients in Brazil for its own phase 3 trial. (The New York Times says a Wuhan-based team has also started a phase 3 trial in the United Arab Emirates.)
- Moderna’s mRNA vaccine has reached phase 2, with phase 3 anticipated for later this month.
- Oddly, the only vaccine already approved for human use is still in phase 2: China has approved CanSino’s vaccine for use in its military. That’s a risky call: A May article in Nature Biotechnology pointed out that CanSino based its vaccine on an adenovirus called Ad5—a vector to which the author estimated 45 percent of Chinese are already immune. That means the vaccine likely wouldn’t work in almost half of the population.
- Six more candidates are in “phase 1/2” status, combining the first two stages of research by automatically proceeding with the highest vaccine dose that did not cause harmful side effects.
Thinking even further outside the box, an Australian-led team is investigating a long-known phenomenon in which the bacillus Calmette-Guérin (BCG) vaccine, used to prevent tuberculosis in the developing world, seems to boost immunity more generally. Could it reduce the chances of severe COVID-19 infection? This team had a head start, since BCG has undergone extensive study over the years. Since the only question is whether it protects against the coronavirus, the team went straight to a phase 3 trial.
If we count the repurposed BCG vaccine along with Oxford’s, Sinovac’s, and Moderna’s coronavirus-specific vaccines, the end of July will likely see four phase 3 trials progressing simultaneously—with several more planned in months to come. Even the first trials won’t finish until fall, and successful mass production doesn’t mean instantaneous availability. But accelerated approval and pre-built factories should limit delays if one or more of the candidates prove worthy.
“This is not the end. It is not even the beginning of the end,” as Churchill once said. “But it is, perhaps, the end of the beginning.”
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In March, a study in Wuhan, China, suggested that coronavirus patients might benefit from a potent steroid called methylprednisolone. But the study’s preliminary nature and its small number of participants limited its impact: At the time, the Eastern Virginia Medical School guidelines, which have helped guide COVID-19 treatment elsewhere, warned that “this topic is controversial” before summarizing the Wuhan findings and suggesting steroids may help.
Now, those findings have received support from the Recovery study, a University of Oxford clinical trial enrolling over 11,500 patients so far at 175 hospitals in the U.K. Recovery is investigating five potential treatments for COVID-19. One arm of the study, with over 2,100 patients, is investigating the steroid dexamethasone. (With hydroxychloroquine eliminated on June 5, the remaining candidates in the study are the anti-HIV combination drug Kaletra, the antibiotic azithromycin, plasma from recovered patients, and an anti-inflammatory called tocilizumab.)
The chief investigators write:
Dexamethasone reduced deaths by one-third in ventilated patients … and by one-fifth in other patients receiving oxygen only. ... There was no benefit among those patients who did not require respiratory support.
Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone.
This is excellent news, for several reasons. The first is obvious: A drug has now demonstrated clinical benefit for COVID-19 patients in a large, well-run trial. The second reason is less obvious but equally significant: Dexamethasone is cheap, easily manufactured, and generally well tolerated in short courses. It lacks the harsh side effects of hydroxychloroquine. Unlike remdesivir, its supply is so plentiful that it is routinely given to prevent nausea in surgical patients. Nor are pharmaceutical patents an issue—dexamethasone has been in clinical use for about 60 years, so generic manufacturers worldwide can produce it.
Every answer in research raises more questions. Steroids are not a single drug but an entire class of them (dexamethasone belongs to the group called glucocorticoids, distinct from anabolic steroids, the drugs weightlifters occasionally abuse to bulk up). Which steroid is best? How much should patients receive, and how often? Should other drugs accompany it, to enhance its effect or to mitigate side effects? How will diabetics, who are prone to severe COVID-19 but whose blood sugar often rises significantly with steroid therapy, fare?
Another logical question is how we should respond, in terms of treatments and preventive efforts. This one is simpler: Outside of the hospital, little needs to change, because dexamethasone does not prevent coronavirus infection. Nor does the drug help minor COVID-19 cases, since it appears to work by tapping the brakes on the “cytokine storm” of an overactive immune system response to the virus. Because of this, patients only benefit from it once their condition is serious enough that they’re in the hospital, receiving oxygen or on a ventilator. (Patients in the Recovery trial showed no benefit from dexamethasone until that point.)
The recent study retractions in The Lancet and The New England Journal of Medicine have hurt public trust in medical research, especially in an environment where statements for or against a given drug often reflect political leanings. A cheap, effective, and uncontroversial drug that truly helps COVID-19 patients is the medical research world’s first step toward regaining its own health.