SCENT Trial: Nasal Theophylline Irrigation for Treatment of Post-Viral Olfactory Dysfunction
Phase: PHASE2
Conditions: Olfactory Disorder, Anosmia, Viral Infection, Theophylline Causing Adverse Effects in Therapeutic Use, Smell Disorder
Sponsor: Washington University School of Medicine

 
 
 
 
 
Smell Changes & Efficacy of Nasal Theophylline (SCENT) 
 
 
 
 
NCT03990766 
 
 
 
Principal Investigator: Jake J. Lee, MD 
 
Institution: Washington University School of Medicine in St. Louis 
 
 
Document Date: April 18, 2019 
 
 

Intranasal Theophylline Irrigation for Treatment of Post-Viral Olfactory 
Dysfunction 
 
Principal Investigator: Jake J. Lee, MD 
 
Short Title: Intranasal Theophylline Irrigation 
 
 
Research Team Members: Jay Piccirillo, MD; Pawina Jiramongkolchai, BA; Daniel Lander, BS; Dorina 
Kallogjeri, MD, MPH; John Schneider, MA, MD; Cristine N. Klatt-Cromwell, MD, Sara Kukuljan, BS, CCRC, RN 
 
Project to be registered on ClinicalTrials.gov 
 
 
ABSTRACT 
Olfactory dysfunction affects approximately 15% of the adult population and significantly impacts quality of life. 
Current available treatments include systemic corticosteroids, intranasal corticosteroids, and olfactory training, 
with limited evidence of efficacy. In vitro and in vivo studies have demonstrated the crucial role of elevated 
cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels in olfactory 
signaling and sensory axonal regeneration. Theophylline, a medication commonly used to treat asthma, 
inhibits phosphodiesterase, thereby increasing cAMP and cGMP levels. This effect on key messengers 
provides a possible mechanistic explanation for theophylline’s role in the treatment of olfactory dysfunction. 
Therefore, we propose a single-site, double-blinded, placebo-controlled randomized clinical trial to evaluate the 
efficacy of intranasal theophylline irrigation on subjective and objective olfaction outcomes in 32 adults with 
post-viral olfactory dysfunction. The study statistician, Dr. Dorina Kallogjeri, will use a randomized block design 
for study drug assignment will use a randomized block design for study drug assignment. The randomization 
scheme will be a 1:1 ratio. The addition of theophylline in a large-volume, low-pressure nasal saline irrigation 
will enhance drug penetration to the olfactory cleft compared to nasal spray. We hypothesize that intranasal 
theophylline irrigation will be more effective in improving olfactory recovery than placebo nasal saline irrigation 
and that there will be minimal systemic absorption and adverse effects. If the results of this phase II study 
suggest that theophylline added to nasal saline lavage improves olfactory dysfunction, then a larger phase III 
randomized controlled trial based on the results from this study can be designed. 
 
1.4 Research Question & Study Aims 
AIM 1: Evaluate the efficacy of intranasal theophylline delivered via high-volume, low-pressure nasal 
saline irrigation on olfactory recovery in patients with post-viral olfactory dysfunction. 
Participants will be randomized to 6 weeks of either theophylline and nasal saline irrigation or nasal saline 
irrigation alone. The primary outcome will be within- and between-subject changes in subjective rating of smell. 
The secondary outcome will be within- and between-subject changes in University of Pennsylvania Smell 
Identification Test (UPSIT) scores. Compared to nasal saline irrigation alone, we hypothesize that intranasal 
theophylline irrigation will be more effective in improving olfactory recovery. 
 
AIM 2: Describe adverse effects related to theophylline nasal saline irrigation. 
All participants will be monitored for adverse effects throughout the study. A subset of participants will undergo 
serum theophylline measurements to assess the level of systemic absorption, if any. Based on prior studies 
which failed to demonstrate detectable serum theophylline levels after intranasal spray, we hypothesize that 
intranasal theophylline irrigation will have minimal systemic absorption and adverse effects. 
 
Background & Significance 
Olfactory dysfunction is a very prevalent condition affecting 15% of all American adults and 25% of 
adults older than 53 years of age.1,2 Commonly, afflicted individuals describe impairments in food preparation 
and diet, weight changes, concerns over environmental safety, poor personal hygiene, impaired interpersonal 
relationships, and social withdrawal, even comparing it to “living a life without color” or “living in a plastic bag”.3 
As a result, those affected have reduced quality of life and increased 5-year mortality.4,5 Most causes of 
olfactory dysfunction are acquired, and etiologies include post-viral, inflammatory such as in chronic 
rhinosinusitis (CRS), traumatic, neurodegenerative such as in Parkinson’s disease, and idiopathic.6 

Post-viral olfactory dysfunction is characterized by sudden loss of smell following an upper 
respiratory infection and is the underlying etiology in up to 40% of patients with olfactory dysfunction, making it 
one of the most common causes of impaired olfaction.7 Up to one-third of patients with post-viral olfactory 
dysfunction have some degree of spontaneous olfactory recovery, but recovery is often incomplete.8,9 Other 
studies revealed lower spontaneous olfactory improvement rates of 18% in this patient population after 7-9 
months, indicating that the natural time course is not clearly defined.10,11 Furthermore, the pathophysiology of 
post-viral olfactory dysfunction is not well understood, thereby frustrating both clinicians and patients. 
 
To add to the frustration, there is no universally effective treatment, leaving many patients with 
olfactory dysfunction feeling hopeless.3 Historically, corticosteroids have been used as an initial treatment 
modality. While multiple studies have demonstrated improvement in olfaction outcomes after systemic 
corticosteroid therapy, most of these studies have low quality of evidence and lack an appropriate control 
group.12-15 The one randomized controlled trial (RCT) of patients with post-traumatic anosmia that compared a 
group treated with oral prednisolone versus a control group receiving no treatment demonstrated no significant 
differences in recovery rates of olfactory function.12  
In addition, two studies, including an RCT (level 1B evidence), on topical corticosteroid treatment with 
nasal spray have demonstrated no significant differences in olfaction outcomes pre- and post-intervention.16,17 
A systematic review examining the efficacy of systemic and topical corticosteroid therapy on non-CRS olfactory 
dysfunction concluded that corticosteroid nasal sprays have no effect on olfaction (level 1B evidence) while 
systemic corticosteroids may improve olfactory loss (level 4 evidence).18 Recently, an RCT comparing 
combined olfactory training and budesonide irrigation to olfactory training alone demonstrated a significantly 
higher improvement rate in objective smell scores via the UPSIT in the combined arm.19 
Olfactory training, without corticosteroid use, is a promising treatment modality based on olfactory 
neuroplasticity. Olfactory training involves repeated exposure to four different odors in an attempt to 
regenerate olfactory receptor cells and recreate the signaling pathway to the olfactory cortex.20 Two meta-
analyses of patients with olfactory dysfunction who completed olfactory training revealed significant 
improvements in odor discrimination and identification scores compared to controls.20,21 
On a molecular level, prior in vitro and 
in vivo studies have investigated the 
importance of cAMP and cGMP as 
secondary messengers in olfactory 
responses. Olfactory neuronal dendrites are 
highly enriched with adenylate cyclase and 
guanylate cyclase, which convert adenosine 
triphosphate (ATP) to cAMP and guanosine 
triphosphate (GTP) to cGMP, respectively 
(Figure 1).22-24 Once odorants attach to 
olfactory receptors, these olfactory neuronal 
dendrites have rapid potent increases in 
adenylate cyclase and guanylate cyclase 
activity, resulting in elevated cAMP and cGMP 
levels.25 Increased levels of these secondary 
messengers result in the opening of sodium 
and calcium ion channels leading to 
depolarization and action potentials for 
olfaction.26  
Fig. 1. The mechanism of action of theophylline, non-selective phosphodesterase inhibitor, on cAMP and 
cGMP signaling, adapted from Barnes PJ.24 
 
In addition to impacting olfactory signaling, cAMP appears to affect sensory axonal regeneration. 
Unlike neonatal axons, adult axons do not regenerate after injury due to the inhibitory effect of myelin and 
myelin-associated glycoprotein (MAG) likely related to the precipitous drop in cAMP levels in dorsal root 
ganglion neurons shortly after birth, which never recovers.27 Elevated cAMP levels appear to increase the 
regenerative capacity of injured sensory axons in vitro and in vivo by blocking the inhibition of axonal 
regeneration by myelin and MAG.28 While the above literature studied spinal cord neurons, cAMP levels may 
also have similar effects in other sensory neurons, such as those involved in olfaction. Henkin and Velicu 
discovered that cAMP and cGMP levels in nasal mucus were significantly lower in hyposmic patients 
compared to normosmic controls.29 Furthermore, a stepwise increase in olfactory dysfunction was 

associated with a stepwise decrease in nasal mucus cAMP and cGMP levels, thereby underscoring the 
potential significance of cAMP and cGMP in the olfactory response.30  
Since phosphodiesterases (PDE) break down cAMP and cGMP into adenosine monophosphate (AMP) 
and guanosine monophosphate (GMP), respectively, investigators have studied the use of PDE inhibitors to 
improve olfaction. Theophylline, an inexpensive and widely available treatment for asthma and chronic 
obstructive pulmonary disease (COPD), is a non-selective PDE inhibitor, thereby increasing intracellular 
levels of cAMP and cGMP which then result in bronchodilation, smooth muscle relaxation, and decreased 
inflammation downstream (Figure 1).24 Its anti-inflammatory properties may also be mediated by its ability to 
prevent the translocation of nuclear factor-κB (NF-κB), a pro-inflammatory transcription factor, into the 
nucleus.31 Due to its dual ability to increase cyclic nucleotide levels and decrease inflammation, theophylline 
offers promise as a newer adjunct to treat olfactory dysfunction. 
In fact in a single-arm longitudinal study of oral theophylline treatment on hyposmic patients, 50% 
(157/312) reported subjective improvement in smell with 11% (34/312) reporting return of normal smell 
function.32 In addition, on objective olfactometry of 4 different odors, there were significant improvements in 
mean odor detection and recognition thresholds. Similar improvements in smell in responders to oral 
theophylline treatment have also been associated with significant increases in brain activation signal in 
response to odors on functional magnetic resonance imaging (fMRI).33 Some patients only responded to 
theophylline in a dose-dependent manner, requiring further escalation of dosing and prolonged treatment 
duration, thereby exposing them to adverse events including headache, nausea, vomiting, lightheadedness, 
tachycardia, abdominal discomfort, and restlessness.24,32 
Due to systemic theophylline’s relatively narrow therapeutic index and desire for improved therapeutic 
efficacy, topical administration of theophylline has also been studied. The same investigators from the single-
arm oral theophylline study conducted a small pilot study on intranasal theophylline spray in 10 patients who 
had submaximal responses to prior oral theophylline treatment.34 Eight of these ten patients reported 
subjective improvement in smell function after intranasal theophylline, and there was a mean 28% increase in 
quantitative subjective scores compared to 14% after oral theophylline, which was a statistically significant 
difference. Objective testing via olfactometry revealed significant improvements in detection and recognition 
thresholds for 4 different odorants. Lastly, serum theophylline levels were undetectable in all patients. A 
more recent abstract detailed a study of 8 patients with chronic anosmia and hyposmia also treated with 
intranasal theophylline spray, of whom 4 of 8 had improvement on subjective and/or objective testing via the 
Monell-Jefferson Taste and Smell Questionnaire and UPSIT, respectively.35 Interestingly, these participants’ 
response to prednisone did not predict response to intranasal theophylline, offering a promising treatment 
modality to patients with olfactory loss refractory to corticosteroid treatment. 
 
Despite the novelty of the two published studies investigating nasal theophylline spray, it is difficult 
interpreting the clinical significance of intranasal theophylline from the data due to the heterogeneity of the 
study populations, non-standard measurement modalities of olfaction, and lack of a control group.34,35 Both 
studies included patients with olfactory dysfunction of multiple etiologies. Henkin et al.’s study population may 
also represent a relatively refractory group since all participants previously either had suboptimal responses to 
oral theophylline or could not tolerate its course, thereby limiting generalizability. Additionally in Henkin et al.’s 
studies on oral and intranasal theophylline, an increase of 5 points on the 100-point scale for quantitative 
subjective smell change was considered clinically significant without sufficient explanation of that 
determination.32,34 Furthermore, Goldstein et al.’s study was limited to an abstract, which categorized people as 
complete responders if they improved on both subjective and objective testing and partial responders if they 
only improved on one without detailing effect sizes or measures of clinically significant change.35 A discussion 
between the PI (Lee) and Dr. Greg Davis, a rhinologist at the University of Washington who was a panelist at 
the New & Improved Treatment Options for Olfactory Loss session at the AAO-HNS 2018 Meeting (Atlanta, 
GA), confirmed the above concerns, thereby putting the published 50% response rate into question. 
 
While topical delivery of theophylline via nasal spray has been studied, there is no literature utilizing 
delivery via nasal saline irrigation. Various additives, including corticosteroids and antibiotics, to irrigation 
devices are gaining popularity as a result of improved distribution of the medication throughout the nasal cavity 
and paranasal sinuses.36 We believe the large-volume, low-pressure nasal saline irrigation delivery system will 
result in better penetration of the middle meatus and olfactory cleft than nasal spray. 
 
 
Participant Population Description 

Participants will be recruited from our institution’s Otolaryngology-Head and Neck Surgery based on the 
following eligibility criteria.  
Inclusion criteria include:  
1) males and females ages 18 to 70 years 
2) subjective or clinically diagnosed olfactory dysfunction of 6 months to 36 months duration after a 
presumed viral upper respiratory infection 
3) ability to read, write, and understand English.  
Exclusion criteria include:  
1) dependence on theophylline for comorbid conditions such as asthma and COPD 
2) history of an allergic reaction to theophylline or other methylxanthines 
3) prior sinonasal or anterior skull base surgery 
4) nasal polyposis 
5) history of neurodegenerative disease (ie. Alzheimer’s dementia, Parkinson’s disease, Lewy body 
dementia, frontotemporal dementia) 
6) pregnant or breastfeeding mothers. 
7) 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. 
 
Individual Data Elements 
 
To determine potential eligibility for the study, we will query the medical record based on the following 
inclusion/exclusion criteria: 
- 
Age (18 to 70 years of age) 
- 
Medication history to assess for dependence on theophylline (exclusion) 
- 
Allergy history to theophylline or other methylxanthines (exclusion) 
- 
Past surgical history for prior sinonasal surgery (exclusion) 
- 
Past medical history for nasal polyposis (exclusion) 
Existing diagnoses of neurodegenerative disease (ie. Alzheimer’s dementia, Parkinson’s disease, Lewy 
body dementia, frontotemporal dementia) (exclusion) 
 
For those meeting the criteria, we will access name, telephone number, age, sex, and date/time of any 
clinic visits related to olfactory dysfunction. 
 
Recruitment and Consent Process 
 
Adult patients with reported smell loss after an upper respiratory infection (URI) with duration between 6 
to 36 months will be recruited from the clinics of the Washington University School of Medicine. Attending 
physicians from both the Departments of Otolaryngology – Head & Neck Surgery and other departments such 
as Internal Medicine will be informed of the study.  
 
Eligible patients who present to clinic will be approached by a research team member to review the 
informed consent process and thoroughly discuss the research protocol, potential benefits, and risks of the 
study with the patient and any available family members in person. Any subsequent questions or concerns 
from the potential participant and any family members will also be addressed at that time. After discussion, the 
patient will be asked to re-summarize the steps involved in the study to ensure understanding. If interested, 
written consent may be obtained during that visit. Patients will be reminded that study participation is voluntary 
and will in no way affect their current or future care. 
 
 
 
Study Procedures 
This study will be a single-site, double-blinded, placebo-controlled randomized clinical trial performed at a 
tertiary academic medical center. The proposed study flow diagram is shown in Figure 2.  
Aim 1: Evaluate the impact of intranasal theophylline delivered via high-volume, low-pressure nasal 
saline irrigation on olfactory recovery in patients with post-viral olfactory dysfunction. 
We hypothesize that intranasal theophylline irrigation will be more effective in improving olfactory 
recovery compared to nasal saline irrigation alone. After enrollment, all patients will undergo anterior 
rhinoscopy at the initial visit to rule out polyps. Enrolled subjects will then undergo baseline olfactory testing 
using:  
 

 
Fig. 2. Proposed study flow. 
 
1) Global Rating of Smell 
Dysfunction. This baseline global rating is 
adapted from the Clinical Global Impressions-
Severity scale to address smell.37 It measures 
the severity of baseline smell loss by asking: 
“Overall, please rate your current sense of 
smell. Response options: Excellent, Very good, 
Good, Fair, Poor, or Absent.” 
2) Modified Questionnaire of 
Olfactory Disorders. A 42-item questionnaire, 
which includes negative statements, positive 
statements, sincerity statements, and parosmia 
statements to evaluate quality of life (QOL) related to olfactory dysfunction. 
3) Veterans RAND 12 (VR-12) Emotional Health Survey. The VR-12 is a widely established 12-item 
questionnaire that evaluates physical and emotional health status. The seven questions pertaining to emotional 
health will be utilized. 
4) University of Pennsylvania Smell Identification Test (UPSIT, Sensonics, New Jersey). The 
UPSIT is a validated 40-question forced-choice odor identification test where microencapsulated odorants on a 
strip are released by scratching.38,39 Out of a total of 40 points, normosmia is defined as ≥34 for males and ≥35 
for females, and an increase in ≥4 points is considered a clinically significant improvement.38  
All enrolled participants will then undergo simple randomization to receive 6 weeks of either 
theophylline 12 mg capsules or identical-appearing placebo lactose capsules. We determined the 
theophylline dose to be 12 mg based on the literature by calculating a ratio using the same concentration of 20 
mcg/0.4 mL that was utilized in the nasal spray.34,35 Using equivalent ratios, 20 mcg / 0.4 mL = X / 240 mL, so 
X = 12,000 mcg = 12 mg dissolved in 240 mL of nasal saline.   
The use of theophylline in a nasal saline rinse is a change in the approved route of administration. An 
exemption from IND requirements is requested as the proposed use of theophylline in this study fulfills all of 
the criteria for exemption: 
1. Theophylline is lawfully marketed in the United States. 
2.  This study is not intended to be reported to the FDA in support of a new indication or  
significant change in labeling. 
3. This study is not intended to support a significant change in the advertising for the  
drug. 
4. The study does not involve a route of administration, dose, patient population, or other  
factor that significantly increases the risk (or decreases the acceptability of the risk)  
associated with the use of theophylline. 
5. The study will be conducted in compliance with the requirements for review by an IRB  
(21 CF R part 56) and with the requirements for informed consent (21 CFR part 50). 
6. The study is not intended to promote or commercialize theophylline. 
 
The placebo product will contain lactose monohydrate and will be supplied in clear plastic capsules, 
which are identical to the theophylline capsules.  The lactose capsule will only contain lactose as there are no 
other ingredients. 
Participants will dissolve the contents of either the theophylline or lactose capsules 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.40 
The primary outcome will be the self-reported Global Rating of Smell Change on a 7-point Likert 
scale, which asks, “Overall, how would you rate your change in smell after your 6 weeks of irrigations? 

Response options: Much better, Somewhat better, Slightly better, Neither better nor worse, Slightly worse, 
Somewhat worse, or Much worse.” Subjects that report a change of slightly better or more will be defined as 
responders to treatment. Efficacy will be determined by the difference in the rate of responders in the two 
intervention arms. Secondary outcomes will be within- and between-subject changes in UPSIT scores from 
baseline to post-intervention.  
 
Aim #2: Describe any adverse effects related to theophylline nasal saline irrigation. 
We hypothesize that systemic absorption of theophylline delivered via nasal saline irrigation will be 
minimal, and thus, there will be minimal adverse effects. One study on intranasal theophylline spray measured 
serum theophylline levels in 10 patients, all of which were immeasurable.34 Following intranasal administration, 
a drug may enter systemic circulation through direct local absorption in the nasal mucosa or oral absorption of 
any swallowed medication.41 If a drug enters the systemic circulation through the nasal mucosa, the medication 
is subject to plasma protein binding, which renders it bio-inactive, reducing the potential for adverse effects. 
Approximately 40% of theophylline is bound to plasma proteins after entering systemic circulation.42    
A portion of the drug may also be cleared into the throat and swallowed, making it available for 
gastrointestinal absorption. Medications absorbed through the gastrointestinal tract are subject to first-pass 
hepatic metabolism, which largely determines the amount of medication that reaches systemic circulation. 
Following oral administration, theophylline does not undergo any measurable first-pass elimination, therefore 
approaching 100% of the available drug.43 
Another factor to account for is the volume of nasal irrigation that will remain in the sinus cavity. In 
patients with chronic rhinosinusitis who undergo nasal saline irrigation with a 240 mL sinus rinse bottle, up to 
5% of the solution remains in the sinuses.44 Therefore, the maximum amount of fluid left in the sinuses after a 
240 mL nasal irrigation is estimated to be 12 mL. Applying this data, the maximum absorption of 12 mg of 
theophylline added to a 240 mL saline filled rinse bottle for irrigation may be estimated by calculating 12 mg / 
240 mL = 0.05 mg/mL or 50 mcg/mL. Since the maximum volume that is estimated to be retained in the 
sinuses is 12 mL, 12 mL x 50 mcg/mL = 600 mcg per dose. For twice daily dosing, the total daily dose is 
1200 mcg or 1.2 mg. 
On average 1 mg/kg of theophylline results in blood levels rising 2 mcg/mL.45 Therapeutic effects of 
theophylline occur at a serum concentration of 5-20 mcg/mL.46 Unwanted side effects, such as headache, 
nausea, vomiting, restlessness, and tachycardia, occur when plasma levels exceed 20 mcg/mL.24 Given the 
available information, a total daily dose of 1.2 mg administered by nasal irrigation should be well tolerated. 
In our study, the first 10 participants will undergo serum theophylline level measurements at the 
end of Week 1. To maintain the blind, 5 participants will be selected from each intervention arm. Assuming the 
time to peak absorption of topical theophylline is similar to oral theophylline, which is 2 hours, we will draw 
serum theophylline levels approximately 2 hours after administration of the nasal sinus rinse with assigned 
capsule. If we identify a measurable amount of theophylline in the serum, we will repeat the test in the same 
subject. If presence of theophylline is detected in the second sample, we will continue to measure in another 
10 subjects to better define the generalizability of the risk of systemic absorption. 
In addition to the serum theophylline level test, all participants will be regularly queried throughout the 
study regarding any adverse effects experienced with the intervention. If theophylline-related adverse effects 
are suspected, the participant will be instructed to stop the medication and present to either the nearest 
emergency department, his/her primary care provider, or the Otolaryngology-Head & Neck Surgery clinic, 
depending on severity of the adverse effect. 
 
Potential 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 post-viral olfactory dysfunction so that 
intranasal theophylline may become a mainstay treatment of this disease which currently has no effective 
treatment. 
 
Analysis Methods 
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 between the two groups 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. 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 
pre-post change in scores between the two groups. Effect sizes with 95% CIs will be reported for each 
analysis. All statistical analyses will be conducted in SPSS 25 (IBM Corp., Armonk, NY). 
 
Rationale or Power Analysis 
To date, there is no study that explores the effect of theophylline in post-viral olfactory dysfunction 
alone, and among the 2 published pilot studies, none utilizes a control group. This phase II study will provide 
us with the needed observed effect size for future phase III RCTs. While pilot data from previous studies 
suggest a 50% response rate after 4 weeks of intranasal theophylline treatment,32,34,35 we believe that 50% is 
overly optimistic from our discussion with Dr. Greg Davis, who prescribes nasal theophylline spray in his 
clinical practice and estimates a more realistic response rate of 25%.  
Thus, unlike a traditional sample size and power calculation, we will instead utilize a fixed sample size 
based on feasibility. At our institution, an annual average of 172 patients presented with ICD-10 code R43 
(Disturbances of smell & taste), and our two full-time rhinologists report seeing a total of 2-5 patients with post-
viral olfactory dysfunction per week, providing a conservative estimate of 100 patients per year. Based on 
these numbers and Dr. Jiramongkolchai’s recruitment rate for CORE grant #575133 (see Preliminary Studies), 
a realistic estimate for enrollment within a 12-month period is 40 participants. With an anticipated 20% drop-
out and withdrawal rate, we estimate 32 participants – 16 in each arm – will complete the study. Based on the 
sample size of 32, we calculated a range of possible effect sizes defined as the difference in rate of responders 
between the two groups and 95% confidence intervals (CI). We assumed two placebo response rates of 6.25% 
(1/16) and 12.5% (2/16) and a reasonable range of intranasal theophylline response rates from 18.75% (4/16) 
to 50.0% (8/16) (Table 1). 
 
Table 1. Effect size and 95% confidence interval (CI) estimates given various combinations of intranasal theophylline and 
placebo saline irrigation response rates for a sample of 32 patients with 16 in each group. 
Hypothetical 
Study 
Result 
Placebo Response 
Rate, 
% 
Intranasal Theophylline 
Response Rate, 
% 
Effect 
Size, % 
Lower Bound of 
95% CI, % 
Upper Bound of 
95% CI, % 
1 
6.25 
50 
43.8 
16.5 
71.0 
2 
6.25 
37.5 
31.3 
4.7 
57.8 
3 
6.25 
25 
18.8 
-5.6 
43.1 
4 
6.25 
18.75 
12.5 
-10.0 
35.0 
5 
12.5 
50 
37.5 
8.1 
66.9 
6 
12.5 
37.5 
25.0 
-3.7 
53.7 
7 
12.5 
25 
12.5 
-14.2 
39.2 
Given the sample size of 32 patients and reasonable rates of response, the upper bound of the 95% CIs for all 
7 hypothetical studies displayed in the Table shows that a clinically meaningful result is plausible in the study 
population and warrants pursuit with future phase III studies using sample sizes based on our study’s effect 
size and precision estimates in order to conclusively test the efficacy of intranasal theophylline irrigation. 
 
Assessment of Treatment Safety 
 
In our study, the first 10 participants will undergo serum theophylline level measurements at the end of 
week 1. To maintain the blind, 5 participants will be selected from each intervention arm. Assuming the time to 
peak absorption of topical theophylline is similar to oral theophylline, which is 2 hours, we will draw serum 
theophylline levels approximately 2 hours after administration of the last nasal sinus rinse with assigned 
capsule. If we identify a measurable amount of theophylline in the serum, we will repeat the test in the same 
subject. If presence of theophylline is detected in the second sample, we will continue to measure in another 
10 participants to better define the generalizability of the risk of systemic absorption.  Treatment safety will also 
be assessed by patient interview and will include collection of adverse events experienced by the patient 
during the six-week participation. 

 
Data and Safety 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 and 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 will be investigated by the monitoring team and reported to Washington University 
HRPO according to the reporting requirements.  
 
 
Participant Remuneration 
Every participant will receive $40 after the initial visit and $40 at the completion of the 6-week study for 
a total of $80. The first ten patients that undergo phlebotomy for serum theophylline measurement at the end of 
the study period will receive an additional $40 for a total of $120. Parking vouchers will also be provided at 
each visit. 
 
Provisions to Protect the Privacy Interests of Participants, Confidentiality and Data 
Management 
Procedures that are in place to curb risks of breaches in confidentiality and patient 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 assigned by the research coordinator; 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; and 4) a locked cabinet to store identified data forms such as completed 
questionnaires and UPSIT exams. 
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. A key to the locked cabinet 
containing identified data forms will also only be available 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. 
A member of the study team will be available by phone or pager 24 hours a day for 7 days a week to 
respond to any concerns or address any adverse events experienced by any study participant.  
 
Calendar of Events 
Study Activity 
Baseline 
(Time 0) 
Week 1 
Weeks 2, 4 
Week 6 
Consent 
X 
 
 
 
Randomization 
X 
 
 
 
Theophylline 
blood draw 
 
X 
 
X 
Global Rating 
of Smell 
Dysfunction 
Questionnaire 
X 
 
 
 
Modified 
Questionnaire 
of Olfactory 
Dysfunction 
X 
 
 
 
VR-12 
Questionnaire 
X 
 
 
 
UPSIT 
X 
 
 
X 
Written 
instructions for 
administration 
of intervention 
X 
 
 
 

Intervention -  
theophylline or 
placebo 
 
X 
X 
X 
Telephone 
Visit (adverse 
event) 
 
 
X 
X 
Participant 
Remuneration 
X 
 
 
X 
 
 
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