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This rarely used antidepressant, long off-patent, has quietly been going through high-quality clinical studies for treatment of COVID-19. It certainly won’t be endorsed or promoted by any deep-pocketed pharmaceutical company, but deserves some attention nonetheless.
Here’s why I think we might finally be onto something with this “repurposed” drug, even after stumbling numerous times with hydroxychloroquine, lopinavir-ritonavir, ivermectin, azithromycin, doxycycline, colchicine, et al.
First, there is a legitimate mechanism of action — actually, multiple mechanisms, as it has anti-inflammatory, anti-platelet, and potentially antiviral activity independent of its psychoactive properties. If you want to get into the weeds, read this nice summary. But of course many drugs have in vitro mechanisms of action that don’t pan out.
Next, Dr. Eric Lenze and colleagues published a small double-blind clinical trial — well-designed and conducted — which showed benefit. Out of 152 participants enrolled, clinical deterioration occurred in 0 patients treated with fluvoxamine vs. 6 (8.3%) patients treated with placebo, a difference that was statistically significant.
But the problem with such small studies is that a tiny shift in outcomes for the treatment group would substantially change the conclusion. In other words, the results were “fragile.” The authors appropriately concluded that further larger studies were necessary.
After this trial, there was an observational study of opt-in versus opt-out fluvoxamine among newly infected workers at a horse racing track. Despite having more symptoms at baseline, the opt-in group receiving fluvoxamine had better outcomes than those who declined treatment — specifically, 0/65 hospitalizations for fluvoxamine, vs. 6/48 who chose observation only.
But the observational nature of this study also couldn’t provide a high enough level of evidence to change practice. What if the people choosing fluvoxamine were just more “health seeking” — and hence healthier — than those who declined, biasing the result? A highly plausible explanation for the results.
Still, these studies got enough attention to warrant further research, and even a spot on 60 Minutes. The research includes the innovative TOGETHER trial, led by a multinational group of investigators primarily in Canada and Brazil.
Here’s the “adaptive” study design, which shows the tested candidate drugs and the novel way the investigators drop unsuccessful treatments:
Eligible participants must have had symptom onset within the previous 7 days, a positive test for SARS-CoV-2, be older than 18, and have at least one risk factor for disease progression. The primary endpoint for these outpatient treatments was a composite of emergency room visits or hospitalizations due to the progression of COVID-19. The participants enrolled in 10 study sites in Brazil.
The group already published the negative results of their first study, showing that neither lopinavir-ritonavir nor hydroxychloroquine prevented progression to hospitalization or death better than placebo — which means those treatments have been appropriately dropped.
Time to move on to the next bracket, which included fluvoxamine, metformin, and ivermectin! Interim results were presented for the first time last week at an NIH meeting. The metformin didn’t do much of anything, and has been dropped; the ivermectin did a bit more, but still nothing practice-changing or statistically significant, with a relative risk of progression of 0.91 (95% confidence interval 0.69-1.19).
But the fluvoxamine treatment was much more promising. Among the 1480 participants randomized, fluvoxamine reduced the risk of disease progression by 29% (thanks to the lead investigator Dr. Edward Mills for this updated slide):
Most of the secondary endpoints also favored fluvoxamine, though the differences were not always statistically significant given the smaller event rate. No data on safety were presented, but Dr. Mills verbally stated that there were no unexpected toxicities.
No, an interim analysis of an ongoing study is not enough to change treatment guidelines — but it’s getting close, especially given the lack of other options and the favorable safety profile. The results are strong enough for the investigators to stop this comparison in this study, and no doubt a pre-print and submitted paper should be coming soon for further review.
Look, we’ve all been burned by promising studies of these repurposed drugs, and it’s quite reasonable to reserve final judgment until we see the complete data, and even other studies. Both the University of Minnesota COVID-OUT study and the NIH’s ACTIV-6 study include fluvoxamine arms.
But this already feels different from hydroxychloroquine and company given the high quality of the research. And it raises many interesting questions, including:
- Would the results be additive to monoclonal antibodies, which we know work well in early disease but remain limited in availability, expensive, and cumbersome to administer?
- How about combined with inhaled budesonide? Or with molnupiravir? (As an ID specialist with a research focus on HIV, you can tell I think combination therapy is a very good thing.)
- Should it be tried in inpatients, especially for those requiring oxygen, for whom anti-inflammatory approaches seem most beneficial?
- Would it work in other countries?
- On a global level, would fluoxetine be just as effective, as this SSRI is far more widely available?
- What should clinicians do now? Should they prescribe fluvoxamine for newly diagnosed patients with COVID-19? If so, for which ones?
No, I don’t have the answers. But this looks like progress, which during a pandemic is always great to see.
Créditos: Comité científico Covid