Smell in COVID-19 and Efficacy of Nasal Theophylline 3
Phase: PHASE2
Conditions: COVID-19
Sponsor: Washington University School of Medicine

 
 
 
 
 
 
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1 
 
 
 
Smell in Covid-19 and Efficacy of Nasal Theophylline (SCENT 3)  
 
Principal Investigator:   
Theresa Tharakan 
 
 
 
 
 
Version Date/Number:  
3.6.2023 (5) 
 
 
 
 
 

 
 
 
 
 
 
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2 
A Introduction 
 
A1 Study Abstract 
 
Olfactory and gustatory disorders (OGDs) are hallmarks of COVID-19 infection. The 
prevalence of COVID-related OGD symptoms ranges from 17-80% depending on viral 
variant, and the prevalence using objective chemosensory testing is likely even higher. 
The median recovery time for olfactory dysfunction is approximately 15 days after 
infection, but these symptoms persist beyond 90 days and 6 months in 15% and 5% of 
patients, respectively. OGDs have numerous adverse effects such as loss of cortical 
gray matter and decrease in quality of life. Intranasal and oral corticosteroids as well as 
olfactory training are currently used to treat post-viral OD; however they have 
demonstrated limited efficacy and there is no current gold standard of care.  
There is no current consensus on the pathogenesis of COVID-related anosmia; however 
evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and 
olfactory signaling may rely on elevated levels of secondary messengers cAMP and 
cGMP. Elevation of cAMP and cGMP is a known effect of theophylline, a 
phosphodiesterase inhibitor used to treat asthma. In our pilot studies of COVID-19 
related OD, a 6-week course of intranasal theophylline led to modest subjective 
improvement in olfactory symptoms compared to placebo. However, olfactory 
neuroepithelium regeneration takes a minimum of 4 weeks and is prolonged in 
inflammatory settings, therefore we believe a longer course of treatment is necessary to 
observe olfactory improvement. Therefore, we propose a phase II single-site, double-
blinded, placebo-controlled randomized clinical trial to test a 12-week course of nasal 
irrigation with intranasal theophylline for patients with COVID-related anosmia.  
 
A2 Primary Hypothesis 
We hypothesize that theophylline irrigation will be more effective than placebo saline 
irrigation for COVID-19 related OD treatment, and that intranasal theophylline use will 
have minimal adverse effects due to limited systemic absorption. 
A3 Purpose of the Study Protocol 
To elucidate the efficacy and safety of intranasal theophylline irrigation in the treatment 
of COVID-19 related OD in comparison to placebo saline irrigation.  
B Background 
 
B1 Prior Literature and Studies 
 
COVID-19 Pandemic. In December 2019, a novel coronavirus, severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2), was identified in association with pneumonia in 
Wuhan China.1-3 As of August 1st, 2020, over 17.5 million people around the world have 
been infected with the resulting illness, termed coronavirus disease 2019 (COVID-19). 
The United States has more cases than any other country, at over 5 million. The 

 
 
 
 
 
 
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3 
numbers continue to grow exponentially.4 The CDC has listed the following key 
symptoms suggestive of illness with COVID-19: cough, shortness of breath or difficulty 
breathing, fever, chills, muscle pain, sore throat, and new loss of smell or taste.5  
 
Anosmia Prevalence in COVID-19. Subjective olfactory dysfunction (OD) has been 
reported in up to 80% of patients with COVID-19, with varying incidence depending on 
viral variant.6,7 Prevalence of OD using objective olfactory testing is likely higher.8 One 
early study in Iran showed that 59 of 60 COVID-19 patients reported some degree of 
objective olfactory dysfunction, as reported by the validated University of Pennsylvania 
Smell Identification Test (UPSIT).9 Using a smartphone-based app (COVID Symptom 
Tracker), another study gathered self-reported symptoms from patients in the UK and 
the US. Their study reported 65% of patients who tested positive for COVID-19 had loss 
of smell or taste, and for 16%, there was no associated fever or cough. Using data from 
over 70,000 patients, they concluded the predictive ability of OD for COVID-19 was 
higher than the predictive ability of either cough or fever, and that the median duration of 
anosmia was about 5 days.10  Preliminary results from the COVID-19 Anosmia Reporting 
tool developed by the American Academy of Otolaryngology-Head and Neck Surgery 
suggests that, out of 237 initial entries, 27% reported OD as their initial symptom, and 
27% of patients had some improvement in OD with a mean of 7.2 days.1 A study of 143 
patients in Italy assessed persistent symptoms of COVID-19 after about 60 days since 
onset of a patient’s first COVID-19 symptom. About 45% of patients presented with 
anosmia in the acute setting, and about 17% of patients continued to report anosmia 60 
days later.11 This data suggests anosmia can persist beyond two months in over a third 
of cases. A meta-analysis of 18 studies with 3699 patients with COVID-related 
chemosensory dysfunction found that the median recovery time for OD is approximately 
15 days, but these symptoms persist beyond 90 days and 6 months in 15% and 5% of 
patients, respectively.12  
 
Based on an estimate in which 25% of new daily cases will experience anosmia 
(average of 111,000 new daily cases in the first week of August 2022 in the US), and 
that 5% will experience permanent anosmia, we predict that over 500,000 patients will 
suffer from chronic OD by August 2023.4 This estimate does not take into account those 
that already suffer from long-term OD currently.  
 
 
Anosmia and Dysgeusia in COVID-19. Current research studies report both anosmia 
(loss of smell) and dysgeusia (loss of taste) related to COVID-19 interchangeably. In 
rare cases SARS-CoV-2 may lead to isolated taste symptoms through direct 
involvement of the gustatory system, but often dysgeusia is related to impaired 
retronasal olfaction (flavor) rather than gustatory sensations (sweet, salty, sour, 
bitter).13,14 Therefore, primarily focusing on treatment for olfactory dysfunction may treat 
both anosmia and dysgeusia.  
 
It is well established that the nasal cavity and the nasolacrimal duct are key entry points 
for SARS-CoV-2;15-17 however there is yet to be a consensus on the exact mechanism 
that leads to COVID-related anosmia.2 It is believed that the virus enters a cell using 
spike protein S1 to adhere to a host ACE2 receptor. ACE2 receptors are expressed 
throughout the nervous system, which may explain the virus’s neurological 
manifestations.2,18 A bulk sequencing study showed expression of both ACE2 and 
TMPRSS2 genes, both thought to facilitate SARS-CoV-2 viral entry, in the olfactory 
mucosa of humans. A single cell sequencing study, confirmed by immunostaining, 

 
 
 
 
 
 
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4 
further suggested higher expression of ACE2 in sustentacular cells, basal stem cells, 
and in pericytes as opposed to olfactory neural cells.19 There is, however, ultrastructural 
evidence that SARS-CoV-2 enters the central nervous system via direct viral damage to 
the olfactory complex as seen via nasal endoscopic dissection at autopsy.20 A case 
study using MRI in a 25-year-old female with COVID-associated anosmia and dysgeusia 
demonstrated signal alteration, suggesting viral brain invasion into the posterior gyrus 
rectus, which is associated with olfaction. The resolution of the anosmia correlated with 
resolution in that signal alteration as well.21 Therefore, preliminary evidence exists for 
COVID-related anosmia affecting nasal epithelial cells, the olfactory neural complex, 
and/or the cortex directly. The resolution of COVID-related anosmia in the majority of 
patients may be related to the unique neuroplasticity the olfactory system exhibits both 
centrally and peripherally.22-24 However for those in whom symptoms persist, it may be 
beneficial to rely on our current understanding of non-COVID-19 post-viral olfactory 
dysfunction to treat COVID-related anosmia. This research into treatments could 
retroactively support our understanding of the exact pathogenesis of the disease as well.  
 
 
Significance and Management of Olfactory Dysfunction. As of 2016 before COVID-
19, about 13 million or 1 in 8 Americans over the age of 40 suffered from a measurable 
smell dysfunction. In total, 3% of all Americans had anosmia or hyposmia, with post-viral 
olfactory dysfunction (PVOD) being the leading cause.25 While often considered a 
benign or innocuous condition, in recent years olfactory loss has in fact been associated 
with an increased 5-year mortality rate, even after accounting for neurologic disease or 
weight loss. Anosmia has even been shown to be more predictive of 5-year mortality 
than cardiovascular disease, cerebrovascular accident, diabetes, heart failure, or cancer 
in older adults.26-29 Olfactory dysfunction is known to cause loss of cortical gray matter as 
well as significantly decreased quality of life due to its inherent importance in taste and 
flavor, memory, and emotion.22,30 OD affected up to 25% of persons over the age of 50, 
and evidence also suggests it may be associated with depression and contribute to the 
anorexia of aging.31-33 While spontaneous recovery is possible in up to one-third of 
patients with post-viral OD, the recovery is often incomplete.34,35  
 
Because of our limited understanding of the exact pathophysiology of permanent 
anosmia, treatment options have been difficult to develop. In the past, oral and 
intranasal corticosteroids were considered a possible treatment to target nasal mucosal 
inflammation; however they are not currently recommended due to lack of clear benefit 
and a number of adverse effects.3,13 Moreover, systemic corticosteroids (particularly 
dexamethasone) are only recommended for acute COVID-19 infection if supplemental 
oxygen is needed, and it is unclear what the effect of steroids would be for COVID-
related anosmia.36 Other medications such as intranasal sodium citrate, intranasal 
vitamin A, or systemic omega-3 fatty acids have shown potential benefit and negligible 
adverse effects in treating olfactory dysfunction; however more research is needed to 
ascertain their use.3  
 
It is well established that the olfactory system exhibits unique neuroplasticity both 
centrally and peripherally. Neurogenesis in the olfactory tract continues throughout our 
lifetime, leading experts to conduct research on olfactory training to modulate neural 
olfactory function. The current first-line treatment for post-viral OD is olfactory training, in 
which a patient is repeatedly exposed to four different odors in an attempt to regenerate 
olfactory receptor cells and recreate the signaling pathway to the olfactory cortex.22 
Olfactory training has been shown to improve odor discrimination and identification score 

 
 
 
 
 
 
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5 
as measured by Sniffin Sticks in comparison to controls.22,37 In non-randomized placebo-
controlled trials of post-viral OD, olfactory training was observed to improve subjective 
smell ratings at 8-16 weeks of treatment, with additional incremental improvements with 
continued treatment up to 24-56 weeks.38,39 However, studies of olfactory training have 
shown varying effectiveness depending on the duration of olfactory dysfunction, the 
concentration and molecular weight of odors used, the duration of therapy, and addition 
of steroid nasal irrigation.40 Olfactory training is currently under investigation for use in 
COVID, but it has not been standardized or recommended for routine clinical practice. 
Therefore, investigation of pharmacologic therapies for COVID related olfactory 
dysfunction is warranted.  
 
The current approach to treating COVID-related anosmia relies on this past knowledge 
of post-viral OD, and has been outlined by Whitcroft, et al. (Figure 1).13 This approach, 
however, is continually evolving, and randomized control trials (RCT) on treatments for 
COVID-related anosmia are ongoing. One three-arm RCT for COVID-related anosmia 
treatments has been approved in which participants are randomized to olfactory training, 
budesonide nasal irrigation, or training with smelling household items (NCT04374474).41 
Other trials are testing omega-3 fatty acids vs placebo (NCT04495816),42 mometasone 
nasal spray vs placebo (NCT04484493)43 , and cerebrolycin injections 
(NCT04830943).44  
 

 
 
 
 
 
 
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6 
 
Figure 1. Possible Approach for the Assessment and Management of Suspected 
Coronavirus Disease 2019 (COVID-19)–Related Olfactory Dysfunction13 
 
 
Use of Theophylline in OD and COVID-related anosmia. Prior in vivo and in vitro 
studies have demonstrated the importance of secondary messengers cAMP and cGMP 
in both olfactory signaling and sensory axonal regeneration.45-47 When odorants attach to 
olfactory receptors, downward signal amplification leads to increases in cAMP and 
cGMP, which then instigate action potentials via sodium and calcium channels.48 This 
results in our sense of olfaction.49 cAMP promotes sensory axonal regeneration by 
blocking the inhibition of axonal regeneration by myelin and MAG, found in most adult 
axons.50 Moreover, cAMP and cGMP levels in nasal mucus were significantly lower in 
hyposmic participants compared to normosmic controls,51 and a stepwise increase in 
olfactory dysfunction was associated with a stepwise decrease in nasal mucus cAMP 
and cGMP levels.52 The use of a phosphodiesterase inhibitor, such as theophylline, that 
prevents the breakdown of intracellular cAMP and cGMP, therefore, has been theorized 
to improve olfaction.53,54 Moreover, two preliminary molecular docking studies showed 

 
 
 
 
 
 
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7 
potential affinity of theophylline derivatives to inhibit two important SARS-CoV-2 
proteins, papain-like protease protein (PLpro) and 3-chymotrypsin-like protease 
(3CLpro), offering promise as a treatment of COVID-19. Further in vivo and in vitro 
studies are needed to evaluate clinical utility.55,56  
 
Clinically, theophylline is an inexpensive drug with FDA approval for the treatment of 
both asthma and chronic obstructive pulmonary disease (COPD).47 Theophylline is a 
methylxanthine that works by smooth muscle relaxation (bronchodilation) and 
suppression of tissue response to stimuli (anti-inflammatory).57 Oral theophylline for OD 
showed subjective improvement starting at 4-6 weeks but with continuing improvement 
for 6-72 months of treatment (Henkin 2008). While systemic theophylline has a narrow 
therapeutic index, the use of intranasal theophylline has recently been studied as a 
potential treatment for post-viral OD at doses that do not  increase serum theophylline 
levels.58 A study on OD of various etiologies demonstrated improved smell detection and 
recognition thresholds after 2 months of 20 ug intranasal theophylline spray (Henkin 
2022). Two pilot studies of participants who had post-viral OD refractory to multiple 
treatments reported statistically significant improvement in quantitative subjective scores 
of smell.58,59  
 
A study at our institution attempted to evaluate the role of intranasal theophylline nasal 
irrigation, as opposed to nasal spray, on post-viral OD. Delivery via nasal irrigation may 
improve penetration into the middle meatus and olfactory cleft compared to the nasal 
spray. This study was conducted at a particularly low dose of 12 mg twice a day and 
reported no clinically or statistically significant differences in olfactory function 
improvement between theophylline nasal irrigation and placebo.  
 
A follow-up dose escalation trial tested higher doses up to 400mg twice daily for safety 
and reported minor side effects in 2 out of 10 participants at the maximum dose thus far. 
One patient reported pre-existing atrial fibrillation for all four weeks of the trial. 4 out of 
10 participants also reported improvements in their sense of smell.  
 
A subsequent trial tested a 6-week course of 400mg theophylline in saline irrigations 
twice daily compared to placebo (lactose in saline irrigation).60 Systemic absorption as 
measured by serum theophylline after 1 week at this dose was negligible. Of 45 
participants who completed the study, Eleven (50%) participants in the theophylline arm 
compared to 6 (26%) in the placebo arm had a clinically meaningful change on objective 
olfactory testing.13 (59%) in the theophylline arm had subjective improvement compared 
to 10 (43%) in the placebo arm, for a difference in response rate of 15.6% (95% CI -13.2 
to 44.5%). This wide confidence interval precludes definitive conclusions but the upper 
bound of 44.5% is much larger than the MCID of 25%, suggesting that the observed 
effect of theophylline on both subjective and objective outcomes warrants a larger trial to 
investigate the efficacy of this treatment more fully.  
 
B2 Rationale for this Study 
COVID-related anosmia is a major symptom of infection with SARS-CoV-2, affecting up 
to 80% of those with COVID-19. While research on the pathogenesis is ongoing, a 
significant subset is expected to suffer from permanent olfactory dysfunction. We seek to 
test intranasal theophylline nasal irrigation as a potential therapeutic option for treatment 
of COVID-related anosmia lasting over 2 months. Theophylline has been shown to 

 
 
 
 
 
 
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8 
improve outcomes in post-viral OD in pilot studies, and our initial data suggests 
therapeutic benefit in patients with post-COVID OD. This phase II placebo-controlled, 
double-blinded RCT will provide us with the needed observed OD treatment effect for 
future phase III RCTs. 
C Study Objectives 
C1 Primary Aim 
Evaluate the efficacy of intranasal theophylline irrigation on olfactory recovery and 
health-related quality of life in patients with COVID-19 related chronic olfactory 
dysfunction. Participants will receive 12 weeks of either theophylline or placebo nasal 
saline irrigation. The primary outcome will be within- and between-subject changes in the 
subjective ratings of smell via the Clinical Global Impression Scale (CGI). A secondary 
measure will be the Olfactory Dysfunction Outcomes Rating (ODOR) survey. 
C2 Rationale for the Selection of Outcome Measures 
In accordance with virtual research protocols, all measurement tests at baseline and at 
the 12-week mark will be administered via online HIPAA-compliant survey. The following 
outcome measures were chosen to evaluate our hypothesis.  
 
Primary Outcome:  
1. Clinical Global Impression Scale (CGI)- We will measure the response rate 
defined as the number of participants self-reporting minimal change or larger in 
the Clinical Global Impression Scale (CGI) scale, divided by the number of 
participants in each group. The CGI has two components – the CGI-Severity and 
the CGI-Improvement. The CGI-Severity Scale from 1-7 (1 is Normal, 7 is 
Complete loss of smell) will provide us with subjective data on the patient’s 
perceived severity of their dysfunction at baseline. The CGI-Improvement Scale 
from 1-7 (1 is Very Much Improved, 7 is Very Much Worsened) will allow us to 
measure changes at 4 weeks and post-treatment at 8 weeks. Each rating is well 
defined to minimize variability.61 Participants reporting 3 as Minimally Improved, 2 
as Much Improved, or 1 as Very Much Improved in the CGI-I will be deemed 
responders to treatment, and the number of responders to non-responders will 
be compared between the two arms. 
 
Secondary Outcomes:  
1. Olfactory Dysfunction Outcomes Rating (ODOR) – ODOR is a new disease-
specific questionnaire that assesses for physical, functional, and emotional 
limitations in participants with olfactory dysfunction of any etiology. Based on the 
recurring impairments for participants with post-viral OD in eating/appetite, 
environmental safety, interpersonal relationships, hygiene, and mood, 28 items 
were generated to create the new patient reported outcome measure. This test is 
expected to be validated in Spring 2021.  
2. COVID-19 related questions – Questions will be asked about the length of time 
since COVID-19 infection, severity of symptoms, previously attempted treatments 
for olfactory dysfunction, and presence of parosmia/phantosmia. This survey will 
help us determine whether the efficacy of theophylline therapy depends on any of 
those factors. 
 

 
 
 
 
 
 
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D Investigational Agent  
D1 Preclinical Data 
Theophylline is a methylxanthine that works by smooth muscle relaxation 
(bronchodilation) and suppression of tissue response to stimuli (anti-inflammatory). It 
non-selectively inhibits phosphodiesterase (PDE) III and IV, thereby increasing 
intracellular cAMP and cGMP levels.47 These secondary messengers then result in 
bronchodilation, smooth muscle relaxation, and decreased inflammation. It also prevents 
the translocation of nuclear factor-κB (NF-κB), a pro-inflammatory transcription factor, 
into the nucleus and thus decreases inflammation even further.57 We hypothesize that 
due to these mechanisms, theophylline could improve olfactory dysfunction by reducing 
inflammation in nasal epithelial cells as well.  
 
There are two preliminary molecular docking studies that used derivatives of 
theophylline to test high-affinity inhibition of three SARS-CoV-2 proteins. Theophylline 
derivatives in particular showed potential affinity for inhibiting papain-like protease 
protein (PLpro) and 3-chymotrypsin-like protease (3CLpro); however in vivo and in vitro 
studies are needed to evaluate future clinical use.55,56  
D2 Clinical Data to Date  
Clinically, theophylline is an inexpensive drug with FDA approval for the treatment of 
both asthma and chronic obstructive pulmonary disease (COPD). Clinical studies show 
conflicting data for its use in acute asthma exacerbations; however in acute COPD 
exacerbations, theophylline may decrease dyspnea, air trapping, and the work of 
breathing.62 It may also improve contractility of diaphragmatic muscles, but it does not 
improve pulmonary function measurements.63,64 Theophylline may be efficacious in 
chronic asthma and exercise-induced bronchospasm, and is an alternative, but not 
preferred, treatment for mild persistent, moderate, and severe asthma.47 Theophylline 
improves respiratory function in COPD in multiple ways and is recommended as daily 
maintenance therapy with beta2-agonists and anticholinergics. It has been shown to 
reduce hematocrit and improve symptoms from chronic hypoxemia and allow for greater 
bronchodilation and reduced diaphragmatic fatigue.47,64 At serum concentrations 
approaching 17 mcg/mL, theophylline has been shown to improve peak flow, trapped 
gas volumes, vital capacity, distances walked, and breathlessness and fatigue.65 Recent 
data suggests a goal serum concentration of 10-15 mcg/mL to achieve clinical efficacy 
without side effects commonly seen at concentrations >20 mcg/mL.25,47 Non-FDA 
approved uses may include nocturnal asthma, newborn apnea, and post-dural punctural 
headache. It has been studied as prophylaxis for acute renal failure, seasonal allergic 
rhinitis, cerebral vasospasm, and more.25 
 
Oral theophylline has also been studied in a single-arm longitudinal trial for the treatment 
of hyposmia in which 50% of patients (157/312) reported subjective improvement in 
smell and taste, and 11% of patients (34/312) even reported return of normal function of 
smell. Mean odor detection and recognition thresholds were also significantly 
improved.53 Oral theophylline use has also been associated with increased brain 
activation signals on fMRI in response to odors.54  
 
Systemic effects of theophylline suggest a relatively narrow therapeutic index.47 These 
effects may be related to phosphodiesterase III inhibition in particular. Common adverse 

 
 
 
 
 
 
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10
effects of theophylline known thus far include headache, nausea, vomiting, tremors, 
insomnia, lightheadedness, and restlessness. Serious adverse effects can include 
tachyarrhythmias, atrial fibrillation, Stevens Johnson syndrome, intracranial hemorrhage, 
and seizure.25,47  
 
It was hypothesized that topical theophylline may be preferred for certain disease states. 
A pilot study of 10 participants who previously had submaximal responses or intolerance 
to oral theophylline were given intranasal theophylline for the treatment of hyposmia and 
hypogeusia. This study showed improved taste and smell acuity in 8 participants after 4 
weeks of intranasal theophylline therapy, reporting a statistically significant mean 
increase of 28% in quantitative subjective scores for smell improvement in comparison 
with 14% for the oral theophylline group. Moreover, serum theophylline levels were 
undetectable in all participants.66 Four of 8 patients with chronic anosmia and hyposmia 
who did not respond to prednisone had improvement of olfactory dysfunction in a pilot 
study with intranasal theophylline spray.59 
 
A trial of 39 patients with olfactory disorders of various etiologies demonstrated a 
statistically significant improvement in smell detection and identification thresholds after 
2 months of 20 mcg intranasal theophylline spray (Henkin 2022).67  
  
A study by our group evaluated the role of intranasal theophylline nasal irrigation, as 
opposed to nasal spray, on post-viral OD. We believe delivery via nasal irrigation 
improves penetration into the middle meatus and olfactory cleft than the nasal spray.68 
Patients with chronic OD were randomized to 12mg twice daily theophylline nasal 
irrigation (n=12) or placebo saline nasal irrigation (n=10). There was no statistical or 
clinical significant difference in objective olfaction identification, but there was a greater 
improvement in QOD-NS in the theophylline group (median difference -10 points, 95% 
CI -15 to -4). Our group hypothesized that the low effect of theophylline on objective 
smell may have been due to underdosing, therefore a dose escalation trial was done to 
test the tolerance of higher doses of intranasal theophylline delivered via nasal irrigation 
for hyposmia and hypogeusia.69 7 out of 10 patients tolerated the maximum dose of 
400mg twice daily without any reported side effects. One patient reported transient minor 
side effects that lasted for one day following increase in dose to 300mg twice daily and 
again at 400mg twice daily. Another patient reported continued tremors, anxiety, and 
abdominal pain after increasing dose to 300mg twice daily and discontinued the study. 
Abdominal pain is not currently a well-known side effect of theophylline use.  The third 
patient reported pre-existing atrial fibrillation throughout the study. 
 
A subsequent trial by our group tested a 6-week course of 400mg theophylline in saline 
irrigations twice daily compared to placebo (lactose in saline irrigation).60 Ten patients 
who underwent serum testing after 1 week of intervention all had serum theophylline 
concentration <5 ug/mL, reflecting negligible systemic absorption. At week 3, the 
theophylline arm had 2 participants reporting insomnia and the placebo arm had 3 
participants reporting tachycardia. Two participants assigned to the theophylline arm 
reported parosmia and foul taste with the intervention resulting in 1 withdrawal and 1 
with poor compliance (>30% of pills remaining at 6 weeks). Of 45 participants who 
completed the study, Eleven (50%) participants in the theophylline arm compared to 6 
(26%) in the placebo arm had a clinically meaningful change on objective olfactory 
testing. Thirteen (59%) in the theophylline arm had subjective improvement compared to 
10 (43%) in the placebo arm, with a difference in response rate of 15.6% (95% CI -13.2 
to 44.5%). This wide confidence interval precludes definitive conclusions but the upper 

 
 
 
 
 
 
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11
bound of 44.5% is much larger than the MCID of 25%, suggesting that the observed 
effect of theophylline on both subjective and objective outcomes warrants a larger trial to 
investigate the efficacy of this treatment more fully. 
 
 
 
D3 Dose Rationale and Risk/Benefits  
 
Previous data suggest a serum concentration between 10-15 mcg/mL will achieve the 
majority of the drug’s potential benefit while minimizing adverse effects for asthma and 
COPD. Adverse effects significantly increase beyond a serum concentration of 20 
mcg/mL, and severe symptoms (seizures, ventricular arrhythmias, and death) has been 
shown to occur in chronic concentrations of 40 mcg/mL or an acute concentration above 
80 mcg/mL.25,47  
 
The dose of oral theophylline used in the treatment trial of hyposmia and hypogeusia 
ranged from 200 mg up to 800 mg a day divided into two equivalent doses (breakfast 
and lunch).53 Some patients only responded to theophylline in a dose-dependent 
manner, at a minimum of 600 to 800 mg, requiring further escalation of dosing and 
prolonged treatment duration. This escalation also meant exposing patients to further 
adverse events associated with theophylline such as headaches. Mean serum levels for 
patients on 800 mg oral theophylline daily was 11.2 +/- 0.8 mg/dL.53  Our institution’s 
low-dose theophylline nasal irrigation trial used 12 mg capsules of theophylline dissolved 
in 240 mL saline twice daily for six weeks, which was the equivalent converted dose 
from the intranasal theophylline spray open-label trial.53 Our follow-up dose escalation 
trial used a maximum daily dose of 800 mg, which was increased from 200 mg daily in 
200 mg increments like the earlier oral theophylline trial did with minimal side effects. 
The systemic of theophylline 800 mg daily via nasal irrigation was clinically negligible 
after 1 week of treatment.  
 
Treatment duration longer than 6 weeks may be necessary to observe olfactory neural 
recovery in the post-infectious setting. Therefore, we propose an 800 mg daily intranasal 
dose with a treatment period of 12 weeks with the expectation of minimal side effects but 
greater treatment efficacy.  
 
 
E Study Design  
 
E1 Overview or Design Summary 
This study will be a single-site, double-blinded, placebo-controlled randomized clinical 
trial performed at a tertiary academic medical center. The purpose of this Phase II trial is 
to evaluate the efficacy of intranasal theophylline irrigation in treating COVID-related 
olfactory dysfunction. This study will also be used to describe adverse effects related to 
intranasal theophylline irrigation. Below is a diagram of the approach to a randomized 
control trial for achieving the specific aims (Figure 2): 
 

 
 
 
 
 
 
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This study will be conducted via virtual research guidelines and procedures. We will not 
require in-person patient participation or evaluation. Following initial evaluation to ensure 
patients meet all inclusion criteria and none of the exclusion criteria, the research study 
will be explained in full via phone call. Participants will then be randomized in a 1:1 
allocation via permuted-block sequencing to the intranasal theophylline irrigation group 
or the intranasal placebo irrigation group. All assessments will be conducted through a 
HIPAA-compliant online survey form. Baseline assessments will help us determine 
subjective and objective rates of olfactory dysfunction. Outcome assessments will be 
conducted at 6 weeks and at 12 weeks, at which point the study will conclude. The 
primary objective of this study is to assess the efficacy of intranasal theophylline 
irrigation in improving COVID-related olfactory dysfunction. 
 
E2 Subject Selection and Withdrawal  
2.a 
Inclusion Criteria  
Participants will be recruited based on the following inclusion criteria:   
1) males and females ages 18 to 75 years 
2) residing within the states of Missouri or Illinois 
3)   Olfactory dysfunction that has persisted for >3 months following suspected 
COVID-19 infection  
4) Baseline University of Pennsylvania Smell Identification Test (UPSIT) 
consistent with decreased olfactory function (<= 34 in women, <=33 in men). This 
test is a clinically validated 40-question forced-choice odor identification test 
where microencapsulated odorants on a strip are released by scratching.70 This 
will determine that patients have both subjectively and objectively diagnosed OD 
prior to undergoing treatment.  
5) Ability to read, write, and understand English and have access to email.  
Participants 
Baseline 
Assessment
1:1 Treatment 
Allocation
Weeks 1-12 
Eligible 
patients with 
COVID-
related 
olfactory 
dysfunction 
(n=240) 
Baseline 
Tests:  
 
CGI-S 
UPSIT 
ODOR 
COVID 
questions 
Outcomes measured at end 
of Week 6 and 12.  
 
Adverse effects reported 
throughout study, check-in 
at weeks 3, 6, 9, and 12. 
 
1° outcome: CGI-I 
2° outcomes: ODOR, side 
effects survey 
Figure 2: Study design 
Theophylline, 1 
cap 400 mg, or 
placebo  
 
2x daily, in 240 
mL nasal saline 
irrigation 

 
 
 
 
 
 
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2.a 
Exclusion Criteria  
Individuals will not be allowed to participate in this study if they meet one or more of the 
following exclusion criteria:  
1) History of olfactory dysfunction prior to COVID-19 infection 
2) Any use of concomitant therapies specifically for the treatment of olfactory 
dysfunction 
3) Use of or participation in previous trials of intranasal theophylline.  
4) Known existence of nasal polyps, prior sinonasal, or anterior skull-based surgery 
5) Dependence on theophylline for comorbid conditions such as asthma and COPD 
6) History of an allergic reaction to theophylline or other methylxanthines 
7) History of neurodegenerative disease (ie. Alzheimer’s dementia, Parkinson’s 
disease, Lewy body dementia, frontotemporal dementia) 
8) Pregnant or breastfeeding mothers. 
9) Current use of medications with significant (≥40%) interactions with theophylline, 
which include cimetidine, ciprofloxacin, disulfiram, enoxacin, fluvoxamine, 
interferon-alpha, lithium, mexiletine, phenytoin, propafenone, propranolol, tacrine, 
thiabendazole, ticlopidine, and troleandomycin. 
 
2.b 
Ethical Considerations  
This project relies on the participation of human subjects. To ensure their safety, we will 
prioritize obtaining informed consent, maximizing benefit and minimizing risk, and 
maintaining confidentiality. Participants will be evaluated by a medical professional 
during the first interaction via phone call. Participants will phone in data or submit online 
surveys at baseline, the 6th week, and the 12th week. Intranasal theophylline has been 
proven to have a minimal side effect profile and results in no detectable serum 
theophylline concentrations to date. The study team will be available at all times in case 
of adverse events, and a participant may remove themselves from the trial at any point 
throughout the trial. No financial conflicts of interest. 
2.c 
Subject Recruitment Plans and Consent Process 
Recruitment will be done at the Washington University Department of Otolaryngology-
Head and Neck Surgery outpatient clinics and the Barnes Jewish Hospital Care and 
Recover After COVID 19 (CARE) Clinic. Advertisements will also be sent to all members 
of the St. Louis ENT Club, otolaryngologists whose practices are within 150 miles of 
Washington University Medical Center (WUMC), members of the Washington University 
Faculty Practice Plan, the BJH Medical Group, and otolaryngologists at academic 
institutions in the state of Missouri, Illinois, and Kansas City, Kansas. Recruitment of 
subjects will also be achieved by sending flyers through the Washington University 
Volunteers for Health Research Participant Registry (VFH), and the Otolaryngology 
Research Participant Registry. Study posters and flyers may be posted around the 
medical campus and on Facebook with the help of VFH. This recruitment strategy has 
been successful for Dr. Jake Lee’s Smell Changes & Efficacy of Nasal Theophylline 
(SCENT) trial (NCT03990766) and SCENT2 trial (NCT04789499). We may also attempt 
to recruit participants from past studies in our lab, such as Dr. Piccirillo’s CODS trial (IRB 
#202004146), Dr. Piccirillo’s NASAL trial (IRB #202010228), and Dr. Piccirillo’s GRACE 
trial (IRB #202110011). Additionally, due to the focus on virtual research at this time, we 
will also post the flyer on websites and social media, including the WUSTL Clinical 
Outcomes Research lab website and Facebook groups for olfactory disorders with 
written permission by Facebook group administrators. We will also work with anosmia 

 
 
 
 
 
 
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14
support groups such as AbScent, FifthSense and the Smell and Taste Association of 
North America (STANA) to share the study flyer.  Lastly, we may use ResearchMatch to 
recruit within Missouri and Illinois. 
 
Contact made by telephone or email from interested individuals to the study team: 
• 
Potentially eligible patients who present to clinic will be given a study flier and 
instructed to contact the study team or begin online screening as indicated on the 
flier. 
• 
Potentially eligible individuals who see the approved study flier 
 
The study team member will introduce the study and gauge interest in participation. 
Interested individuals will be asked to complete an online screening questionnaire to 
ensure he or she meets all of the inclusion criteria and none of the exclusion criteria. 
Interested individuals will also have the option to complete the first step of online 
screening on REDCap via a QR code link from the study flier.  
 
Following eligibility confirmation, an informed econsent will be acquired. Questions will 
be encouraged from the individual. This may occur during the telephone call or at a 
mutually agreeable time. If the individual wishes to participate they will proceed with the 
econsent providing signature and initials where indicated in the form. The signature will 
be time stamped and the participant will receive a copy of the signed consent (electronic 
file). Appropriate technical securities will be followed to protect the confidentiality of the 
participant’s information including sending a test email to confirm the email address. A 
study team member will be on the phone with the individual during the econsent process 
and available by email or phone following should they have questions. No coercion or 
undue influence will be exercised. Individuals will be informed that participation is 
voluntary and that they can withdraw at any time during the study with no consequences. 
 
Any modifications to the project resulting in consent form changes will be tracked by the 
study team. In the event re-consent is required, the change is made to the econsent 
form in REDCap and the econsent process is conducted again with the participant as 
described.  
 
The following privacy protections will be enacted for all email communications involving 
PHI: 
1) emails will be encrypted according HIPAA Privacy Office standards by 
including [secure] in subject line or 
2) PHI will not be included in the email or subject line, but will be sent as a 
password protected attachment. The password for the attachment will be 
provided to the subject separately (in a separate email, by phone, or by 
letter) 
 
Retention of identifiable information on non-consented individuals will be kept for contact 
purposes for future research opportunities. 
 
2.d 
Randomization Method and Blinding 
Subjects will be randomized in a 1:1 allocation via permuted-block sequencing to the 
intranasal theophylline irrigation group or the intranasal placebo irrigation group. This 

 
 
 
 
 
 
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15
trial will be double-blinded, meaning neither the subjects nor the study team will be 
aware of the intervention received by any subject.  
2.e 
Risks and Benefits 
The potential benefit to the participant is improvement of their smell and taste using this 
novel therapy. The potential benefit to the society is the use of the results to initiate a 
large phase III study to definitively determine efficacy of intranasal theophylline use for 
treatment of COVID-related olfactory dysfunction. If effective, intranasal theophylline 
would become a mainstay treatment of this disease, which currently has no effective 
treatment. The potential risk to the participant is an adverse event related to the use of 
intranasal theophylline. Common adverse effects of systemic theophylline known thus 
far include headache, nausea, vomiting, tremors, insomnia, lightheadedness, and 
restlessness. Serious adverse effects can include tachyarrhythmias, atrial fibrillation, 
Stevens Johnson syndrome, intracranial hemorrhage, and seizure. Intranasal 
theophylline has shown minimal adverse effects.  
2.f 
Early Withdrawal of Subjects  
The consent process informs a volunteer about the study, indicates that participation is 
voluntary, and that he/she has the right to stop at any time. Risks are enumerated in the 
informed consent form and described orally during the consent process. Subjects will be 
allowed to end participation in the study at any point should they desire. If a participant 
must be withdrawn due to a drug-related serious adverse event, the study drug will be 
stopped immediately. They will have an exit interview to ascertain any adverse effects 
and discuss the reason for the ending participation. The study team will follow them for 
safety reasons up to 30 days after stopping use of the study drug.  
 
If a subject has ended participation for any reason, the only data that will be collected 
are the data from the exit interview and the data collected prior to withdrawal within the 
12-week time period. There will not be any other follow-up or data collected from these 
subjects.   
 
A participant can withdraw consent for the study at any time. Data collected up to this 
point will not be used in the analysis, and further data will not be collected from these 
subjects.  
 
E3 Study Drug  
3.a 
Treatment Regimen  
Participants will dissolve the contents of the 400 mg theophylline capsules 
(experimental) or identical-appearing lactose capsules (control) into the sinus rinse bottle 
containing nasal saline. All participants will receive an 8-ounce sinus rinse bottle and a 
12-week supply of USP Grade Sodium Chloride & Sodium Bicarbonate Mixture (pH 
balanced, Isotonic & Preservative & Iodine Free) commercially prepared packets. 
Participants will either need to purchase distilled water or boil tap water for five minutes 
for use with the saline irrigation. A member of the research team will instruct participants 
on how to irrigate each nasal cavity with one-half of the contents of the sinus rinse bottle. 
Written instructions and a video demonstration will also be provided to ensure proper 
technique. Because the half-life of theophylline in healthy adults (16-60 years) is 8.7 

 
 
 
 
 
 
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16
hours and 9.8 hours in the elderly (> 60 year), irrigations will be performed twice daily – 
once in the morning and once at night for all subjects,71 for a total daily dose of 800mg 
theophylline nasal irrigation.  
 
3.b 
Preparation and Administration of Study Drug  
After faxing a signed prescription, the compounding pharmacy will formulate and directly 
ship the study drug regimen to the participant’s provided mailing address via FedEx or 
via the United States Postal Service if the patient only has a PO box. All packages in 
transit can be monitored via the tracking numbers. 
3.c 
Subject Compliance Monitoring  
Participants will be evaluated at 6 weeks and at 12 weeks to ensure compliance with the 
study drug regimen as a self-reported measure. As a part of the REDCap surveys, 
patients will be asked whether they have been compliant with twice daily irrigations thus 
far, and what issues have arisen, if any.  
3.d 
Prior and Concomitant Therapy  
Participants receiving concomitant therapy specifically for the treatment of olfactory 
dysfunction will not be eligible for the trial unless they are able to stop taking those 
therapies. Participants who have tried previous therapies for their olfactory dysfunction 
(including over-the-counter treatments such as vitamin A or omega-3 fatty acids) will be 
eligible for the trial. Information will be gathered on their use of therapies, and if needed, 
a sensitivity or subgroup analysis may be considered.  
 
F Study Procedures  
 
F1 Screening for Eligibility 
 
Identified patients through chart review as well as interested individuals who reach out 
after seeing the approved study flier will be contacted via email or phone call to 
introduce and explain the study. Interested individuals will be asked to complete an 
online screening questionnaire to ensure he or she meets all of the inclusion criteria and 
none of the exclusion criteria. Potential participants will also be able to begin the online 
screening questionnaire in REDcap via a QR code provided on the study flier, in which 
case they will receive contact from the study team after completing the first part of 
screening. Following eligibility confirmation, an informed e-consent will be acquired. 
F2 Timeline of Measurements 
Following the recruitment period, randomization of subjects will occur one week prior to 
the start of the trial. The timeline of measurements can be seen in Figure 3. 
 

 
 
 
 
 
 
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17
 
Figure 3. Timeline of measurements for SCENT3.  
2.a 
Start of trial  
Throughout the week before the first day of the trial, baseline tests will be administered 
as described in Figure 1. Participants will be mailed the UPSIT packet and will be 
required to complete all assessments prior to the first day of the trial through an online 
secure survey platform. A member of the study team will be available for any questions 
or concerns. Participants will also be provided instruction on how to properly conduct 
intranasal saline irrigation with theophylline or placebo. Participants will then receive the 
study drug by mail and will report their start date of nasal irrigation.  
 
2.b 
Assessment of blind and adherence 
Participants will be contacted via online secure survey platform or telephone within the 
first 3 weeks of initiating nasal irrigations and asked, “To which arm of the study do you 
think you were randomized?” Choices will be “theophylline and nasal saline irrigation” or 
“nasal saline irrigation alone”.  
 
Participants will also be asked, “In the last 7 days, how many rinses have you 
completed? (For example, if you did 2 rinses every day for 7 days, the total would be 
14).”  
 
2.c 
3-week and 9-week check-ins 
Participants will be contacted via telephone and asked about adverse effects and any 
difficulties with adherence to medication. Adverse event forms will be filled out if adverse 
events are reported.  
Eligibility 
Confirmati
on
Randomizati
on with 1:1 
Allocation
Week 0: 
Start trial, 
baseline 
questions
Week 1-3: 
Blind 
assessed
Week 3: 
Report 
adverse 
effects
Week 6: 
Outcome 
questions; 
report 
adverse 
effects
Week 9: 
Report 
adverse 
effects
Week 12: 
End trial; 
repeat 
outcome 
questions; 
report 
adverse 
effects

 
 
 
 
 
 
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18
2.d 
6-week interaction 
At the 6th week of the trial, participants will repeat assessments as according to Figure 2 
and submit them via online secure survey platform. Efficacy of theophylline nasal 
irrigation for 6 weeks can then be compared to efficacy at 12 weeks. They will also be 
asked to report any adverse events.  
2.e 
End of trial 
At the 12th week of the trial, patients will repeat assessments as described in Figure 2 
and submit them via online secure survey platform. They will also be asked to report any 
adverse events. They will also be asked to count how many capsules are left in their 
bottle as a measure of adherence. This will conclude participation in the clinical trial.  
 
F3 Safety and Adverse Events  
3.a 
Safety and Compliance Monitoring 
The specific monitoring plan for this study is based on the potential risk of participation 
and size and complexity of the planned investigation.  Based on these considerations, 
this study will have a monitoring board comprised of Dr. Piccirillo, Ms. Kukuljan, and Dr. 
Kallogjeri, the study biostatistician. The monitoring board will meet to review data at least 
every 6 months.  All reports of a Serious Adverse Event (SAE) or an Unexpected 
Adverse Event (UAE) will be investigated by the monitoring team and reported to 
Washington University HRPO according to the reporting requirements.  
 
The PI and the study team will be monitoring patients for any safety concerns, such as 
SAE or UAE, in real time for the duration of the 12-week study. In addition, patients will 
be specifically asked about any adverse events at the 3-week, 6-week, 9-week, and 12-
weeks via phone conversation. Participants will also be able to get in touch with a 
member of the study team 24/7 via phone or pager for the duration of the 12-week 
clinical trial. An adverse event form will be completed if a participant indicates an 
adverse event during phone check-ins or at any other time. The study statistician will 
hold the randomization codes, and in the event of an SAE or UAE in which the blind 
needs to be broken, the patient will receive immediate care and will be removed from the 
trial. A description of the event will be included in the report of adverse events for the 
clinical study. 
 
Participants who experience serious adverse effects with theophylline therapy will be 
removed from the study. Participants with serious adverse effects, such as arrhythmia 
and seizures, will be instructed to call 911, seek immediate medical care and discontinue 
all further theophylline treatment. If tolerated, all participants will complete a total of 12 
weeks of treatment. 
 
G Statistical Plan  
 
G1  Sample Size Determination and Power 
 

 
 
 
 
 
 
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19
In our previous phase II randomized placebo-controlled trial of nasal theophylline 
irrigation for post-COVID OD, we set a minimal clinically important difference (MCID) of 
25% in the rate of patients with subjective improvement within the experimental group 
compared to the placebo group. We observed subjective improvement rates of 59% 
(13/22) in the theophylline arm and 43% (10 of 23) in the placebo arm, with a difference 
in response rate was 15.6% (95% CI -13.2 to 44.5%). The upper bound of 44.5% was 
much larger than the MCID of 25%, suggesting the potential for a clinically meaningful 
effect of theophylline despite this statistically insignificant measurement.  
 
For a clinically definitive study with a feasible sample size of 200 participants, the true 
difference in proportions would need to be at least 29% such that the 95% CI around this 
difference has a lower bound of at least 15% (upper bound 41%).  
 
Accounting for a 20% dropout rate, we plan to enroll 240 patients. The sample size of 
240 patients is feasible based on the August 2022 numbers of new COVID-19 cases in 
Missouri (average of 1400 daily new cases) and Illinois (average of 4,300 daily new 
cases) with a conservative estimate of 10% rate of chronic olfactory dysfunction. Using a 
20% drop-out and withdrawal rate, we estimate that the sample size of 240 patients will 
provide us with 200 evaluable cases.  
 
 
G2 Analysis Plan 
An intention-to-treat analysis will be used where all participants will be examined in the 
groups to which they were initially assigned regardless of the treatment actually 
received. Standard descriptive statistics will be used to assess the demographics, 
clinical characteristics, and olfactory test results of the study population. The difference 
in rate of responders at 12 weeks will estimate the effect size of the primary outcome 
measure, and the 95% CI around that point estimate will measure precision. In each 
group, the frequency and relative frequency of the participants’ response to the global 
rating of smell change will be reported for each Likert category. Fisher’s exact test will be 
used for comparing the responders’ rates between the 2 groups at 6 weeks and at 12 
weeks. Histograms and Shapiro-Wilks test will be used to test the normal distribution 
assumption of the continuously measured ODOR scores and the differences pre-post 
treatment in each of the groups. Independent samples t-test or its nonparametric 
equivalent Mann-Whitney U test will be used to compare the change in ODOR scores 
between the two groups. A mixed model analysis will be used to compare the change in 
outcomes through different study assessments between the study groups. Effect sizes 
with 95% CIs will be reported for each analysis. All statistical analyses will be conducted 
in SPSS 27 (IBM Corp., Armonk, NY). 
 
G3 Missing Outcome Data 
Maximum efforts will be made to limit the number of missing values. Missing outcomes 
will be taken into consideration at the beginning of each analysis. Valid percentages will 
be reported alongside overall percent for standard descriptive statistics, and data for 
participants who do not complete the full 12-week trial will be excluded for per-protocol 
analyses. 
 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
20
H Data Handling and Record Keeping  
 
H1 Confidentiality and Security 
Procedures that are in place to curb risks of breaches in confidentiality and privacy are 
1) formal training protocols centered on the maintenance of confidentiality for all study 
team members; 2) secure storage for identified data forms such as completed 
questionnaires and UPSIT exams; and 3) communication with study team via secure 
email, phone line, or televideo call. 
 
Only members of the study team will have access to the computer file and password for 
the master list. All research data files will be stored on secure Washington University 
servers with computer, network, and database-level passwords that will only be 
accessible to study team members. Accordingly, these mechanisms intend to limit 
access to information that can link clinical data to individual subjects. No subject 
identifying information will be revealed in any publications or presentations. 
 
 
I Study Monitoring, Auditing, and Inspecting  
 
I1 
Study Monitoring Plan  
The Principal Investigator (PI) will be responsible for ensuring participants’ safety on a 
daily basis and for reporting Serious Adverse Events and Unanticipated Problems to his 
or her Institutional Review Board (IRB) as required.  
 
J Study Administration 
 
J1 Subject Stipends or Payments  
Subjects will receive $80 at the completion of the 12-week study. If they stop the study 
early but complete at least 3 weeks of the study, they will be paid $10 for time and effort. 
If they complete at least 6 weeks, they will be paid an additional $10 ($20 total). If they 
complete at least 9 weeks, they will be paid an additional $20 ($40 total). If they stop the 
study earlier than 3 weeks, they will be thanked for their time and effort without monetary 
payment. 
 
J2 Study Timetable 
 
August-October 2022: IRB approval process and acquisition of resources 
November 2022: Rolling recruitment 
December-April 2023: 12-week clinical trial 
May-June 2023: Statistical analysis and publication of results 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
21
 
K Publication Plan  
 
We plan to analyze the accumulated data throughout the months of March to May 2023 
and publish results by the end of June 2023. This data includes an analysis of the results 
of the CGI-I and ODOR questionnaires as well as a discussion of potential adverse 
effects related to intranasal theophylline irrigation for treatment of COVID-related 
olfactory dysfunction.  
L Attachments  
 
 
L1  Informed consent documents 
 
 
L2  Questionnaires or surveys 
• 
Clinical Global Impression Scale (CGI) 
• 
Olfactory Dysfunction Outcomes Rating (ODOR) survey 
• 
Screening questions, baseline questions, and follow-up questions (attached) 
 
 
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