Fluvoxamine for COVID-19 outpatients: for the time being, we
might prefer to curb our optimism
Vladimir Trkulja
Running head : Fluvoxamin and COVID-19 outpatients
Key words : fluvoxamine, COVID-19, outpatients, hospitalizations
Vladimir Trkulja, MD, PhD
Department of Pharmacology
Zagreb University School of Medicine
Šalata 11
10000 Zagreb, Croatia
e-mail:
vladimir.trkulja@mef.hr
Number of words: 613
Number of figures/tables: 1
To the Editor,
A rather elaborate pharmacodynmics rationale 1 and
sound pharmacokinetic reasoning 2 support the use of
fluvoxamin in early phases of the COVID-19 disease. Two recent
meta-analyses, 3, 4 both based on the same three
randomized placebo-controlled trials, emphasized the benefit of early
fluvoxamine treatment in non-vaccinated adult symptomatic mild COVID-19
outpatients in terms of a reduced risk of disease deterioration over
subsequent days. In the first of the meta-analyzed trials, Stop COVID 15, primary outcome was hospitalization or incident
hypoxemia needing oxygen treatment within 15 days. The trial was rather
small, particularly for a binary outcome (fluvoxamine 2x100 to 3x100
mg/day over 15 days, n=80; placebo n=72) and recorded only 6 events (all
with placebo) 5. Stop COVID 2 6followed the same design/outcome, and was stopped at an advanced stage
for operational reasons but did not indicate any benefit [incidence
11/272 (4.0%) fluvoxamin vs. 12/275 (4.4%) placebo)]. The
meta-analytical pooled estimates 3, 4 were dominated
by the results of the TOGETHER trial 7 (fluvoxamine
2x100 mg/day, 10 days) that reported a marked relative reduction in the
risk of the primary outcome (emergency room stay of at least 6 hours or
hospitalization; over 28 days): 79/741 (11.0%) vs. 119/756 (16.0%),
RR=0.69 (95% CrI 0.53-0.90) 7. By far the most events
were hospitalizations, but no clear-cut benefit was obvious in this
respect [75/741 (10.0%) vs. 97/756 (13.0%), OR=0.77 (0.55-1.05)7]. The meta-analysis by Lee et al.3 focused on hospitalizations and reported a 25%
relative risk reduction by a frequentist method (RR=0.75, 95%CI
0.58-0.97), while the Bayesian analysis (weakly informative neutral
prior) indicated somewhat more uncertainty (RR=0.78, 95%CrI 0.58-1.08;
81.6% probability of RR ≤0.90) 3. Guo et al.4 employed only frequentist pooling to indicate a
marked benefit regarding “study-defined outcomes” (RR=0.69 95%CI
0.54-0.88) and somewhat more uncertainty regarding “hospitalizations”
(RR=0.79, 95%CI 0.60-1.03) 4. In the meantime, a
report was pubslihed of a randomized placebo-controlled trial conducted
in 2020 in Korean outpatients (∼10 days of fluvoxamine 2x100 mg/day)8. It was stopped early for operational reasons8, and the primary outcome (as in Stop COVID trials)
was observed in 2/26 treated and 2/26 placebo patients8. Figure 1 depicts meta-analysis of “study-defined
primary outcomes” and of “hospitalizations” that uses the same
frequentist and Bayesian methodology as used by Lee et al.3 except that (i) it includes the Korean data8 and (ii) employs Hartung-Knapp-Sidik-Jonkman
correction shown to yield the least biased confidence interval coverage
with small number of trials considerably varying in size9: (a) uncertainty about the benefit regarding
“study-defined outcomes” (Figure 1A) is indicated by both the
frequentist and Bayesian intervals extending to >1.0 and
prediction intervals extending well >1.0. Probability of at
least 10% relative risk reduction is 90.0%; (b) uncertainty about the
benefit regarding “hospitalizations” (Figure 1B) is even more obvious,
with estimate intervals exceding >1.10 (and further
extended predictions intervals), with only 73.8% probability of at
least 10% relative risk reduction. If one were to disregard two small
trials with a few events (and, hence, fragile estimates that could have
been by chance, at least in part) 5, 8, for the time
being one would be looking at Stop COVID 2 and TOGETHER trial. This
means 86/1013 hospitalization events with fluvoxamine vs. 109/1031
events with placebo, and a considerable uncertainty about any
practically relevant effect: (i) frequentist RR=0.803 (95%CI
0.422-1.530); (ii) Bayesian RR=0.840 (95%CrI 0.613-1.170) and only
67.4% probablity of at least 10% relative risk reduction. Hopefully,
the on-going trials (depicted in ref. 3) will resolve this uncertainty,
but presently we might prefer to be cautios rather than overtly
optimistic about the actual extent of benefit conveyed by early
fluvoxamine treatment in COVID-19 outpatients.