Background: Loss of sense of smell is a hallmark of COVID-19 infection. While about 80%
of post-COVID olfactory dysfunction (OD) will experience some spontaneous recovery within
2 months of initial infection, about 20% will continue to suffer long-term.1 Participants
with persistent OD suffer great disability including loss of pleasure with eating leading
to weight loss and/or gain and other health risks, including possible dementia. Further,
loss of smell may lead to harm, with chief examples of inability to smell gas leaks or
food that has gone bad. Currently, use of "smell retraining" is recognized
internationally as the most accepted method to treat patients with OD, including
post-viral or post-infectious OD.2 Some authors have extrapolated that smell retraining
may be of benefit in post-COVID OD, however, data is sparse.3

Increased extracellular calcium has been shown to inhibit the olfaction cascade occurring
in the nose by either phosphorylating adenylate cyclase or by interacting and decreasing
cyclic nucleotide-gated channels sensitivity to cyclin nucleotides. Several studies have
been performed to date using sodium citrate administered as a nasal spray to effectively
reduce extracellular calcium resulting in temporary sense of smell benefit in those who
have smell loss from a variety of causes, most significantly, post-viral or
post-infectious loss (PIOD).

Several studies over the last two decades have examined the effect of sodium citrate on
olfactory function in those with OD (mainly post-infectious OD) all of which have shown
acute improvement in smell, peaking typically around 1 hour after application.4-7 Most
recently, in 2021 Whitcroft et al conducted a controlled clinical trial on 60 PIOD
participants. They applied sodium citrate intranasal spray to participants' right nostril
for two weeks and olfaction was evaluated by Sniffin' Sticks composite TDI score both
before the trial and after 2 weeks of sodium citrate use. They found a significant
improvement in TDI score, though not reaching clinical significance. Further, while the
proportion of participants reporting parosmia did not change, there was a significant
reduction in participants reporting phantosmia.8

The hypothesis is that the administration of sodium citrate to the nasal cavity,
providing a temporary improvement in sense of smell, before the performance of smell
retraining may augment its effects and yield better recovery in post-COVID-19 OD.

Purpose: The goal of this pilot study is to assess the feasibility and impact of using
sodium citrate nasal spray as an adjunct to olfactory retraining in participants with
long-term post-COVID-19 olfactory dysfunction.

Participants: Adults (> 18 years) with > 3 months of subjective olfactory loss.

Methods: All participants will undergo initial smell testing with the University of
Pennsylvania Smell Identification Test (UPSIT) to confirm smell loss before enrollment.

Following screening and consent, enrollment will involve collecting participant data such
as medication allergies, time between COVID-19 infection and smell loss, previous smell
loss therapies tried, presence of gustatory dysfunction, and use of paxlovid.
Participants; olfaction will then be objectively evaluated using "Sniffin' Sticks," a
validated psychophysical tool that allows for more detailed assessment of odor threshold,
discrimination, and identification.

Participants will be randomized into two groups and blinded. The Sodium Citrate arm will
apply a nasal spray of sodium citrate (0.5 mL per nostril) and then perform olfactory
training exercises, twice a day for 12 weeks The Normal Saline arm will apply a spray of
normal saline (0.5 mL per nostril) and then perform olfactory training exercises, twice a
day for 12 weeks. Olfactory training will involve mindful inhalation of 4 primary
odortants (lavender, clove, eucalyptus, and lemon), at least 20 seconds for each.

All materials will be provided by AdvancedRx, who will also perform the randomization to
ensure investigators are blind as well. Nasal sprays will be shipped in 1-month
quantities and adherence will be checked at the end of each month by assessing the amount
of spray left in each bottle. During the 12 weeks, at days 7, 28, and 56, investigators
will contact the participants to discuss if any adverse events have occurred.

At the end of the 12 weeks, "Sniffin' Sticks" assessment will be repeated, and results
compared within and between the groups. Also, the number of eligible participants
encountered, the number enrolled, the number who completed the study, the adherence rate,
and the adverse event rates will be assessed within the overarching 1 year study period.