Conditions: Covid19 Anosmia Olfactory Disorder Covid-19 Pandemic SARS-CoV-2 Infection Hyposmia Ageusia Hypogeusia
Keywords: Smell Smell loss smell dysfunction olfactory dysfunction COVID-19 anosmia theophylline nasal irrigation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 51
Healthy volunteers: no

Brief summary:
Evidence of COVID-19 related anosmia and dysgeusia continues to accumulate daily.

Currently, up to 80% of patients report subjective olfactory dysfunction (OD), and prevalence using objective olfactory testing could be even higher.

We propose a phase II single-site, double-blinded, placebo-controlled randomized clinical trial to determine the efficacy and safety of intranasal theophylline, a known phosphodiesterase inhibitor in the treatment of asthma, as a possible treatment for COVID-19 related OD. Theophylline has shown benefit in similar clinical trials for post-viral OD.

Detailed description:
Post-viral olfactory dysfunction has numerous known adverse effects such as loss of cortical gray matter and decrease in quality of life. COVID-19 related olfactory dysfunction has already been shown to be correlated with depression and decreased quality of life, so finding an effective treatment is imperative.

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, a known effect of theophylline. In this phase II treatment trial, patients will be allocated 1:1 to receive either intranasal theophylline irrigation or placebo for six weeks. Various smell surveys and scratch-and-sniff tests will be utilized to capture changes in smell ability.

Due to COVID-19, this study will be conducted virtually, except for the first ten enrolled patients who will undergo one serum theophylline test. This study is limited to patients living in Missouri or Illinois.

Arms:
arm 1: 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily for six weeks. arm 2: 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily for six weeks.

Interventions: intervention 1: Theophylline Powder intervention 2: Placebo Comparator
Intervention descriptions: intervention 1: Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water. intervention 2: Twice daily nasal irrigation with 500 mg lactose powder capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
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1 
 
 
 
Smell in Covid-19 and Efficacy of Nasal Theophylline (SCENT 2)  
 
Principal Investigator:   
Jay Piccirillo, MD, FACS 
 
 
 
 
 
Version Date/Number:  
2.20.21, V2 
 
 
 
 
 


 
 
 
 
 
 
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2 
A Introduction 
 
A1 Study Abstract 
Evidence of COVID-19 related anosmia and dysgeusia continues to accumulate daily.  
Currently, up to 80% of patients report subjective olfactory dysfunction (OD), and 
prevalence using objective olfactory testing could be even higher. Anosmia and 
dysgeusia are often comorbid in this disease. Preliminary results from the COVID-19 
Anosmia Reporting tool developed by the American Academy of Otolaryngology-Head 
and Neck Surgery suggests that 27% of patients had some improvement in OD with a 
mean of 7.2 days. Prevalence of permanent anosmia from COVID-19 has yet to be 
elucidated, however preliminary studies suggest over a third of patients may not recover 
for over two months since acute infection. Post-viral OD has numerous known 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, a known effect of theophylline. Therefore, we propose a 
phase II single-site, double-blinded, placebo-controlled randomized clinical trial to test 
the use of nasal irrigation with intranasal theophylline, a known phosphodiesterase 
inhibitor in the treatment of asthma, to treat COVID-19 related OD. Theophylline has 
shown benefit in similar clinical trials for post-viral OD.  
 
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 
numbers continue to grow exponentially.4 The CDC has listed the following key 


 
 
 
 
 
 
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3 
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. New olfactory dysfunction (OD) has been reported 
in up to 80% of patients with COVID-19. Prevalence using objective olfactory testing 
could be even higher. 6 One 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).7 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 olfactory dysfunction 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.8  
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 olfactory dysfunction as their initial symptom, and 27% of 
patients had some improvement in OD with a mean of 7.2 days. 1 A recent 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. 9 This data suggests anosmia can persist beyond two months in over a third 
of cases. Based on a conservative estimate in which 50% of new daily cases will 
experience anosmia (average of 215,000 new daily cases in the first week of January 
2021 in the US), and that 10% will experience permanent anosmia, we conclude that 
almost 968,000 patients may suffer from permanent olfactory dysfunction by April 2021.4 
This estimate does not take into account those that already suffer from long-term OD 
currently or those that will continue to be infected after April 2021.  
 
 
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. While 
it may be possible that SARS-CoV-2 directly affects olfactory and gustatory symptoms, 
our current understanding of olfactory dysfunction suggests that dysgeusia is related to 
impaired retronasal olfaction (flavor) rather than gustatory sensations (sweet, salty, sour, 
bitter). 10 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;11-13 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.2,14 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, 
further suggested higher expression of ACE2 in sustentacular cells, basal stem cells, 
and in pericytes as opposed to olfactory neural cells. 15 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.16 A case 
study using MRI in a 25-year-old female with COVID-associated anosmia and dysgeusia 


 
 
 
 
 
 
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4 
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.17 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.18-20 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.21 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.22-25 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.18,26 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.27-29 While spontaneous recovery is possible in up to one-third of 
patients with post-viral OD, the recovery is often incomplete.30,31  
 
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.3,10 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.32 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.18 
Olfactory training has shown significant improvements in odor discrimination and 
identification scores in comparison to controls; however treatment is still not 
definitive.18,33  
 
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).10 This approach, 


 
 
 
 
 
 
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5 
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).34 
Another compares the use of omega-3 fatty acids or placebo (NCT04495816),35 and one 
more uses mometasone nasal spray or placebo (NCT04484493).36  
 
 
Figure 1. Possible Approach for the Assessment and Management of Suspected 
Coronavirus Disease 2019 (COVID-19)–Related Olfactory Dysfunction10 
 
 
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.37-39 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.40 This 
results in our sense of olfaction.41 cAMP promotes sensory axonal regeneration by 
blocking the inhibition of axonal regeneration by myelin and MAG, found in most adult 


 
 
 
 
 
 
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6 
axons.42 Moreover, cAMP and cGMP levels in nasal mucus were significantly lower in 
hyposmic participants compared to normosmic controls,43 and a stepwise increase in 
olfactory dysfunction was associated with a stepwise decrease in nasal mucus cAMP 
and cGMP levels.44 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.45,46 Moreover, two preliminary molecular docking studies showed 
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.47,48  
 
Clinically, theophylline is an inexpensive drug with FDA approval for the treatment of 
both asthma and chronic obstructive pulmonary disease (COPD).39 Theophylline is a 
methylxanthine that works by smooth muscle relaxation (bronchodilation) and 
suppression of tissue response to stimuli (anti-inflammatory).49 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.50 Two pilot studies of participants who had post-viral 
OD refractory to multiple treatments reported statistically significant improvement in 
quantitative subjective scores of smell. 50,51  
 
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. Therefore, a study 
should be conducted to test the use of 800mg daily theophylline irrigation for the 
treatment of COVID-19 OD.  
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 
improve outcomes in post-viral OD in pilot studies, and the effects on placebo group for 
a similar study is already known. This phase II placebo-controlled, double-blinded RCT 
will provide us with the needed observed OD treatment effect for future phase III RCTs. 


 
 
 
 
 
 
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7 
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 6 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). Secondary 
measures include measurements of health-related quality of life via the 36-Item Short 
Form Health Survey, the clinically validated University of Pennsylvania Smell 
Identification Test (UPSIT), the Olfactory Dysfunction Outcomes Rating (ODOR) survey, 
and a Questionnaire for Olfactory Dysfunction  survey (QOD). 
C2 Secondary Aim 
Describe the adverse effects of intranasal theophylline irrigation. All participants will be 
monitored for adverse effects throughout the study. A subset of participants will be 
tested for systemic absorption via serum theophylline measurements after one week of 
therapy. Based on prior studies to safely escalate the intranasal theophylline dosage, we 
hypothesize that intranasal theophylline irrigation will have minimal systemic absorption 
and adverse effects. 
 
C3 Rationale for the Selection of Outcome Measures 
In accordance with virtual research protocols, all measurement tests at baseline, at the 
3-week mark, and at the 6-week mark will be administered via online HIPAA-compliant 
survey. The UPSIT strips will be mailed to participants in advance. 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.52 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. University of Pennsylvania Smell Identification Test (UPSIT) – This test is a 
clinically validated 40-question forced-choice odor identification test where 
microencapsulated odorants on a strip are released by scratching. Out of a total 
of 40 points, normosmia is defined as ≥34 for males and ≥35 for females, and an 
increase in ≥4 points will be deemed a clinically significant improvement in 


 
 
 
 
 
 
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8 
symptoms.53 While the primary outcome is subjective, this test allows for an 
objective measure of olfactory dysfunction and improvement. 
2. 36-Item Short Form Health Survey (SF-36) - The SF-36 is a well-established 
36-item questionnaire evaluating physical functioning, bodily pain, role limitations 
due to physical health problems, role limitations due to personal or emotional 
problems, emotional well-being, social functioning, energy/fatigue, and general 
health perceptions.54 This test allows us to study the overall quality of life 
changes for those suffering from COVID-19 related OD.  
3. 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.  
4. Questionnaire for Olfactory Dysfunction (QOD) – QOD will measure changes 
in the health-related quality of life of participants based on four factors as outlined 
by Mattos, et al. This will qualify which factor (eating, mental health, social 
interactions, or fear of dysfunction) was affected most by the proposed 
intervention. The survey also includes questions on parosmia, a phenomena of 
COVID-related OD.55  
5. 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. 
 
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.39 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.49 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.47,48  


 
 
 
 
 
 
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9 
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.56 It may also improve contractility of diaphragmatic muscles, but it does not 
improve pulmonary function measurements.57,58 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.39 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.39,58 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.59 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.39,60 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.60 
 
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 even (34/312) reported return of normal function of 
smell. Mean odor detection and recognition thresholds were also significantly 
improved.45 Oral theophylline use has also been associated with increased brain 
activation signals on fMRI in response to odors.46  
 
Systemic effects of theophylline suggest a relatively narrow therapeutic index.39 These 
effects may be related to phosphodiesterase III inhibition in particular. Common adverse 
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.39,60  
 
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.61 Four of 8 patients with chronic anosmia and hyposmia 
who did not respond to prednisone had improvement of olfactory dysfunction in another 
study with intranasal theophylline spray.51 
 
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 than the nasal spray. 
Patients with chronic OD were randomized to 12mg twice daily theophylline nasal 


 
 
 
 
 
 
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10
irrigation (n=12) or placebo saline nasal irrigation (n=10). There was no statistical or 
clinical significant difference in olfaction outcomes, except for QOD-NS which favored 
the theophylline group, between the two groups; however a follow-up dose escalation 
trial was done recently to test the use of higher doses of intranasal theophylline 
delivered via nasal irrigation for hyposmia and hypogeusia. 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. An other 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. 
 
There have been no current clinical studies on the use of theophylline in COVID-related 
anosmia and dysgeusia.  
 
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.39,60  
 
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).45 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.45  Dr. Jake Lee’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.45 Dr. Lee’s 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. 
Moreover the bioavailability of theophylline via nasal irrigation is expected to be lower 
than that of oral theophylline. Therefore, we propose the use of 400 mg theophylline 
nasal irrigation twice daily in comparison to placebo. Serum theophylline levels will be 
measured at one week for a subset of subjects. Results will be inspected immediately 
upon receipt of lab report, and appropriate action will be taken as defined in the Medical 
Monitoring section (Section 3.b). 
 
E Study Design  
 


 
 
 
 
 
 
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11
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): 
 
 
 
 
This study will be conducted via virtual research guidelines and procedures. We will not 
require in-person patient participation or evaluation apart from one serum theophylline 
measurement after one week of the trial for up to the first twenty participants who enroll 
in the trial. 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. Assessments will be conducted again at 3 weeks and at 6 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 70 years 
2) residing within the states of Missouri or Illinois 
Participants 
Baseline 
Assessment 
1:1 Treatment 
Allocation 
Weeks 1-6 
Eligible 
patients with 
COVID-
related 
olfactory 
dysfunction 
(n=40) 
Baseline 
Tests:  
 
CGI-S 
UPSIT 
QOD 
SF-36 
ODOR 
COVID 
Outcomes measured at 
end of Week 3 and 6.  
 
Adverse effects reported 
throughout study. 
 
1° outcome: CGI-I 
2° outcomes: UPSIT, 
QOD, ODOR, side effects 
survey
Figure 2: Study design 
Theophylline, 1 
cap 400 mg, or 
placebo  
 
2x daily, in 240 
mL nasal saline 
irrigation 
Serum theo levels 
measured after 
week 1 for 20 pts.  


 
 
 
 
 
 
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12
3)   Olfactory dysfunction that has persisted for >3 months following suspected 
COVID-19 infection  
4) initial score on the UPSIT consistent with decreased olfactory function (<= 34 
in women, <=33 in men)  
5) ability to read, write, and understand English.  
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) History of olfactory dysfunction of longer than 12 months 
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. 
10) Pre-existing arrythmias or seizures (at least until serum blood measurements 
show minimal systemic levels of theophylline or lower)  
 
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 3rd week, and the 6th 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 patient 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. 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 
nearby academic institutions. 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). We may also attempt to 


 
 
 
 
 
 
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13
recruit participants from past studies in our lab, such as Dr. Piccirillo’s CODS trial (IRB 
#202004146) and Dr. Piccirillo’s NASAL trial (IRB #202010228). 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. We will also work 
with anosmia support groups such as AbScent and FifthSense to share the study flyer.  
Lastly, we may use ResearchMatch to recruit within Missouri and Illinois. 
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 
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 
6-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.  
 


 
 
 
 
 
 
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14
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 
6-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 
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,62 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 patient’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  
Patients will be evaluated at 3 weeks and at 6 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 arised, if any.  
3.d 
Prior and Concomitant Therapy  
Patients 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. Patients 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 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 


 
 
 
 
 
 
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15
exclusion criteria. 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. 
 
 
Figure 3. Timeline of measurements for SCENT2.  
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. One week following 
use of therapy, up to the first twenty participants will undergo a serum theophylline 
measurement, which marks the only in-person requirement for this trial.  
2.b 
3-week interaction 
At the 3rd 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 3 weeks can then be measured to efficacy at 6 weeks. They will also be 
asked to report any adverse events.  
Eligibiliy 
Confirmation
Randomization 
with 1:1 
Allocation
Week 0: Start 
of trial, 
baseline 
assessments 
completed
Week 1: 
Serum 
theophylline 
measured
Week 3: 
Repeat 
outcome 
assessments 
and report 
adverse 
effects
Week 6: End 
of trial, 
repeat 
outcome 
assessments 
and report 
adverse 
effects


 
 
 
 
 
 
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16
2.c 
End of trial 
At the 6th 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. 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 6-week study. In addition, patients will be 
specifically asked about any adverse events at the 3-week and 6-week mark via 
REDCap. Participants will be able to get in touch with a member of the study team 24/7 
via phone or pager for the duration of the 6-week clinical trial. 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. 
 
Serum theophylline levels will be measured in the first ten participants of the trial. If any 
subject has a serum theophylline level greater than 20 mcg/mL,39,60 the study will be 
discontinued. If serum theophylline levels are unable to be detected or very minimal ( <5 
mcg/mL), the study will continue with no modifications. If any subject has detectable 
serum theophylline levels >5 mcg/mL, ten more participants will undergo serum 
theophylline testing.  
 
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 6 
weeks of treatment. 
 
G Statistical Plan  
 
G1  Sample Size Determination and Power 
 
To date there have been no studies investigating efficacy of theophylline in COVID-19 
related OD. Due to the lack of preliminary data and effect size, estimates of the sample 


 
 
 
 
 
 
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17
size for this study will be determined based on feasibility. For this pilot study, we plan to 
enroll 50 subjects. The sample size of 50 subjects is feasible given the current numbers 
of new COVID-19 cases in Missouri (average of over 3,500 daily new cases in 
December 2020),63 taking into account a conservative estimate of a 10% rate of 
permanent olfactory dysfunction. Using a 20% drop out rate we estimate that the sample 
size of 50 subjects will provide us with 40 evaluable cases. 
 
A 50% rate of improvement with intranasal theophylline was reported in a pilot study for post-
viral OD;51 however discussion with Dr. Greg Davis, who prescribes nasal theophylline spray in 
his clinical practice, led Dr. Lee to estimated a more realistic response rate of 25%. In Dr. Lee’s 
trial of participants with post-viral olfactory dysfunction, 30% of the participants randomized to 
placebo reported improvement at the end of the trial as compared to baseline. Assuming that 
this will be the response rate in the placebo group of our trial, the sample size of 20 subjects per 
group will provide us with a 95% Confidence Interval -5% to 55% around the desired proportion 
difference of 25% between theophylline and placebo groups.  The upper limit of confidence 
interval suggests that there is real value in the response rate of theophylline in the population. 
The effect size calculated from this study will be used for sample size calculations for future fully 
powered studies.  
We anticipate no more than a 20% drop-out or withdrawal rate, which is included in our 
calculation of sample size.  
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 6 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 3 weeks and at 6 
weeks. Histograms and Shapiro-Wilks test will be used to test the normal distribution 
assumption of the continuously measured UPSIT 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 UPSIT 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 percents will be 
reported alongside overall percent for standard descriptive statistics, and data for 
participants who do not complete the full 6-week trial will be excluded for further 
analyses. 
 


 
 
 
 
 
 
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18
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) de-identified databases using only the study ID numbers; 3) a 
password-protected computer file of a master list that contains the identity of subjects, 
corresponding ID numbers, and contact information but no clinical information; 4) secure 
storage for identified data forms such as completed questionnaires and UPSIT exams; 
and 5) 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 $40 after the initial consultation and serum theophylline 
measurement at 1 week and $40 at the completion of the 6-week study for a total of $80.  
 
J2 Study Timetable 
 
January-February 2021: IRB approval process and acquisition of resources 
February 2021: Rolling recruitment 
February-April 2021 : 6-week clinical trial 
May 2021: Statistical analysis and publication of results 
 


 
 
 
 
 
 
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19
K Publication Plan  
 
We plan to analyze the accumulated data throughout the months of March to May 2021 
and publish results by the end of May 2021. This data includes an analysis of the results 
of the CGI-I, UPSIT, ODOR, and 36-SF 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) 
• 
36-Item Short Form Health Survey 
• 
Olfactory Dysfunction Outcomes Rating (ODOR) survey 
• 
Questionnaire for Olfactory Dysfunction  survey (QOD) 
 
M References 
 
 
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