On Cytokines, Fluvoxamine and COVID-19 – Part 2
Jon-Emile S. Kenny MD [@heart_lung]
“Apocalypse is played out now on a personal scale; it is not in the sky above us, but in our bed.”
With a proposed pathway coupling pathogen-associated molecular patterns to the elaboration of pro-inflammatory cytokines, sketched lightly in part 1, this segment ties murine biomolecular theory to human clinical practice.
As remarked at the end of part 1, Dr. Angela Reiersen was intrigued by the work of Rosen and colleagues and wondered if Fluvoxamine, a sigma-1 receptor agonist, might ameliorate inflammatory unrest in early COVID-19. With this hypothesis, a fully-virtual, outpatient, double-blinded, randomized, controlled trial took shape with results published last fall in the Journal of the American Medical Association by Lenze and colleagues.
Thereafter, a racetrack physician in Berkeley California, aware of the provocative, aforementioned trial, offered fluvoxamine to 113 of his patients during a mass outbreak of SARS-CoV-2 within congregate living. He recently published this prospective, observational data in Open Forum Infectious Diseases.
What they did
Lenze and colleagues enrolled adults who were living in the community with less than 7 days of symptomatic COVD-19 [confirmed SARS-CoV2 infection] and oxygen saturation of at least 92%. Patients were randomized to either fluvoxamine thrice daily or placebo for 15 days.
Patients were excluded for having COVID-19 that required hospitalization or oxygen saturation less than 92% on room air when randomized, severe underlying lung disease, decompensated cirrhosis, NYHA class III or IV congestive heart failure, or were immunocompromised.
Study supplies were delivered as a package left at an enrolled participant’s door – these supplies included the study medication/placebo, a pulse oximeter, an automated blood pressure monitor, and a thermometer. Participants then self-assessed and received calls from blinded study coordinators to record signs and symptoms.
Participants received a dose of 50 mg of fluvoxamine [or matching placebo] on day 1, then 100 mg twice daily as tolerated for two days which was then increased to 100 mg 3 times daily as tolerated through day 15.
The primary end point required both the 1.) presence of dyspnea or hospitalization for dyspnea or pneumonia and 2.) oxygen saturation less than 92% on room air or supplemental oxygen to maintain oxygen saturation of at least 92%.
What they found
152 patients were randomized and the primary end-point occurred in 0 of 80 patients in the fluvoxamine group and in 6 of 72 [8.3%] patients in the placebo group. There was no difference in adverse drug events between the fluvoxamine and placebo groups.
In the prospective, observational study by Seftel and Boulware – where 65 and 48 outpatients opted to take fluvoxamine or not, respectively – hospitalization was 0% with fluvoxamine and 12.5% with observation alone. Within the latter group, two persons required intensive care unit stay with mechanical ventilation, 1 of whom died.
The randomized trial comparing fluvoxamine to placebo is, solely in its conception and execution, a great and laudable feat. Certainly, performing a fully-virtual, outpatient, randomized, placebo-controlled trial during a pandemic is great science and, in my opinion, much more useful than the hordes of retrospective, observational, time-to-intervention, associative studies that fill most virtual journal pages today. While the sample size is relatively small and a noteworthy limitation, the results, nonetheless, demand attention.
Beyond the criticisms outlined in the comments section of the on-line publication [i.e., anti-platelet properties of SSRIs, anti-inflammatory properties of SSRIs, anxiolytic properties of SSRIs, etc.], I cannot help but compare this trial to that of casirivimab and imdevimab versus placebo; i.e., Weinreich et al. In that study, three arms each received 90 patients – randomized to placebo or two different doses of the monoclonal antibodies. Those enrolled were outpatients and the end-points were 1. Change in viral load and 2. The percentage of patients who had at least one COVID-19-related medically-attended visit across 29 days of follow-up. Medically-attended visits were defined as: telemedicine visits, in-person physician visits, urgent care or emergency department visits, and hospitalization. Infusion of antibodies versus placebo reduced medically-attended visits by 3% and this was statistically-significant. In the pre-specified sub-group of enrolled patients who were serum antibody negative at the time of randomization, the medically-attended risk reduction favoured treatment with monoclonal antibodies by 9%, though this sub-fraction of patients totalled 113.
Therefore, the patient populations between the two trials are remarkably similar. Further, in the pre-specified sub-group of antibody negative patients, who Weinreich et al. felt were most likely to benefit from early infusion of monoclonal antibodies, the number of patients studied is quite similar to Lenze et al. Arguably, the main outcome of Lenze and colleagues is more clinically meaningful – requiring both dyspnea and supplemental oxygen to maintain saturation above 92% [essentially a criterion for corticosteroid administration]. Whereas, a ‘medically-attended visit’ may have been a simple telemedicine call.
The supplemental, prospective, observational investigation published by Seftel and Boulware is notable in that their results echo the clinical benefits of the RCT. Nevertheless, the key criticism of their observational study is that there could be a lurking variable explaining the observed difference and that opting for or against fluvoxamine may be a marker of that unknown mechanism rather than any drug effect. Yet their results are given slightly more credence nested within the murine study by Rosen and colleagues and the RCT above.
Fortunately, the Stop COVID Trial [StopCovidTrial.com; email@example.com ClinicalTrials.gov: NCT04668950] is enrolling to help better clarify the role of this widely-available, inexpensive, oral, sigma-1 receptor agonist. Should this trial replicate fluvoxamine as beneficial, one wonders if fluvoxamine expands its role beyond COVID-19 to septic inflammation more broadly?
Fluvoxamine is indisputably cheaper than activated protein C.
Dr. Kenny is the cofounder and Chief Medical Officer of Flosonics Medical; he is also the creator and author of a free hemodynamic curriculum at heart-lung.org. Download his free textbook here.