Smell Changes & Efficacy of Nasal Theophylline

• Theophylline (Drug): Theophylline delivered via high-volume, low-pressure nasal saline irrigation
• Saline Nasal (Drug): Lactose delivered via high-volume, low-pressure nasal saline irrigation

Primary outcomes

• Number of Patients With Improvement in Global Rating of Smell Change [6 weeks]: Self-reported change in smell after intervention on a 7-point Likert scale. Response options with corresponding point values: 7) Much better, 6) Somewhat better, 5) Slightly better, 4) Neither better nor worse, 3) Slightly worse, 2) Somewhat worse, and 1) Much worse. The maximum score is 7, and higher values indicate better outcomes. A score of 4 is considered neutral. Scores of 5 or higher indicated clinical improvement.

Secondary outcomes

• University of Pennsylvania Smell Identification Test (UPSIT) Total Score Change [6 weeks]: Within- and between-subject changes in UPSIT total scores measured at baseline and at 6 weeks after therapy. This test is a validated 40-question forced-choice odor identification test where microencapsulated odorants on a strip are released by scratching. Each question corresponds to one point, and there are no subscales. The minimum score is 0 while the maximum score is 40, and higher values indicate better outcomes.
• Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) Score Change [6 weeks]: Within- and between-subject changes in QOD-NS scores measured at baseline and at 6 weeks after therapy, which is a validated 17-item questionnaire about quality of life and impairments related to olfactory dysfunction. Each question is scored from 0 to 3 points, and there are no subscales. The minimum score is 0 while the maximum score is 51, and higher values indicate worse quality of life or higher degree of impairment.
• Olfactory Dysfunction Outcomes Ratings (ODOR) Score Change [6 weeks]: Within- and between-subject changes measured at baseline and at 6 weeks after therapy. This test is a new disease-specific 28-item questionnaire that assesses for physical, functional, and emotional limitations in patients with olfactory dysfunction of any etiology. Each question is scored from 0 to 4. The minimum score is 0 while the maximum score is 112, and higher values indicate higher degree of limitations and worse outcomes. There are no subscales within the current questionnaire.

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

* Subjective or clinically diagnosed olfactory dysfunction of 6 months to 36 months duration after a presumed viral upper respiratory infection
* Ability to read, write, and understand English

Exclusion Criteria:

* Dependence on theophylline for comorbid conditions such as asthma and chronic obstructive pulmonary disease
* History of an allergic reaction to theophylline or other methylxanthines
* Prior sinonasal or anterior skull base surgery
* Nasal polyposis
* History of neurodegenerative disease (ie. Alzheimer's dementia, Parkinson's disease, Lewy body dementia, frontotemporal dementia)
* Pregnant or breastfeeding mothers
* 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

Participant flow

Outcome results

• Number of Patients With Improvement in Global Rating of Smell Change (Primary), Count of participants, Participants: Theophylline 4; Placebo 3
• University of Pennsylvania Smell Identification Test (UPSIT) Total Score Change (Secondary), Median, score on a scale: Theophylline 1 (-4 to 12); Placebo 0 (-8 to 5)
• Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) Score Change (Secondary), Median, score on a scale: Theophylline -6.5 (-15 to 4); Placebo 1.5 (-4 to 19)
• Olfactory Dysfunction Outcomes Ratings (ODOR) Score Change (Secondary), Median, score on a scale: Theophylline -1.5 (-18 to 6); Placebo -7.5 (-29 to 6)

Adverse events

Time frame: Adverse event data were collected over 6 weeks of treatment

Other adverse events by term

Limitations and caveats: The diagnosis of PVOD is by patient history and is thus subject to recall bias. In addition, PVOD treatment response may differ according to the causative virus, which is rarely known. The sample size was limited since all non-life saving clinical research and recruitment were halted at our institution at the time due to COVID-19. Lastly, the optimal dosing of theophylline irrigations is yet to be determined.

• Study Protocol and Statistical Analysis Plan (PDF, 2019-04-18)
• Informed Consent Form (PDF, 2021-01-15)