Olfactory Disorder, Anosmia, Viral Infection, Theophylline Causing Adverse Effects in Therapeutic Use, Smell Disorder
Conditions
Keywords
Olfactory dysfunction, Anosmia, Hyposmia, Post-viral, Theophylline, Adverse effects, Smell
Brief summary
This study evaluates the efficacy and safety of nasal theophylline irrigation in treating smell loss related to a viral respiratory infection. Half the participants will undergo nasal theophylline irrigation treatment while the other half will undergo placebo nasal irrigation with saline alone. All participants will have their sense of smell tested before and after 6 weeks of treatment. All participants will also be regularly asked about any potential side effects related to treatment. In addition, the first 10 participants will have their blood drawn to measure their theophylline level after 1 week of starting treatment to ensure it is not abnormally elevated.
Interventions
DRUGTheophylline
Theophylline delivered via high-volume, low-pressure nasal saline irrigation
DRUGSaline Nasal
Lactose delivered via high-volume, low-pressure nasal saline irrigation
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blinded
Intervention model description
Two randomized arms
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Theophylline Saline Irrigation Theophylline 12 mg capsule contents dissolved into a sinus rinse bottle containing distilled or boiled tap water and USP Grade Sodium Chloride & Sodium Bicarbonate Mixture commercially prepared packets, delivered to the bilateral nasal cavities twice daily.
Theophylline: Theophylline delivered via high-volume, low-pressure nasal saline irrigation | 12 |
| Placebo Saline Irrigation Identical-appearing lactose monohydrate capsule contents dissolved into a sinus rinse bottle containing distilled or boiled tap water and USP Grade Sodium Chloride & Sodium Bicarbonate Mixture commercially prepared packets, delivered to the bilateral nasal cavities twice daily.
Saline Nasal: Lactose delivered via high-volume, low-pressure nasal saline irrigation | 10 |
| Total | 22 |
Baseline characteristics
| Characteristic | Theophylline Saline Irrigation | Placebo Saline Irrigation | Total |
|---|---|---|---|
| Age, Continuous | 57.5 years | 59.5 years | 59.0 years |
| Body Mass Index | 32.3 kg/m^2 | 33.0 kg/m^2 | 33.0 kg/m^2 |
| Deviated septum | 3 Participants | 2 Participants | 5 Participants |
| Diabetes mellitus | 1 Participants | 1 Participants | 2 Participants |
| Family history of dementia | 2 Participants | 1 Participants | 3 Participants |
| Hypothyroidism | 3 Participants | 1 Participants | 4 Participants |
| Moderate/severe comorbidity (ACE-27 scores 2-3) | 5 Participants | 1 Participants | 6 Participants |
| Obstructive sleep apnea on positive airway pressure | 2 Participants | 0 Participants | 2 Participants |
| Prior nasal steroids | 9 Participants | 7 Participants | 16 Participants |
| Prior olfactory training | 1 Participants | 2 Participants | 3 Participants |
| Prior oral steroids | 8 Participants | 6 Participants | 14 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 9 Participants | 20 Participants |
| Region of Enrollment United States | 12 participants | 10 participants | 22 participants |
| Sex: Female, Male Female | 8 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 8 Participants |
| Smoking history | 0 Participants | 2 Participants | 2 Participants |
| Time from upper respiratory infection to treatment | 11.0 months | 8.4 months | 8.8 months |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 13 |
| other Total, other adverse events | 0 / 14 | 0 / 13 |
| serious Total, serious adverse events | 0 / 14 | 0 / 13 |
Outcome results
Primary
Number of Patients With Improvement in Global Rating of Smell Change
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.
Time frame: 6 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Theophylline | Number of Patients With Improvement in Global Rating of Smell Change | 4 Participants |
| Placebo | Number of Patients With Improvement in Global Rating of Smell Change | 3 Participants |
95% CI: [-35.6, 42.3]
Secondary
Olfactory Dysfunction Outcomes Ratings (ODOR) Score Change
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.
Time frame: 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Theophylline | Olfactory Dysfunction Outcomes Ratings (ODOR) Score Change | -1.5 score on a scale |
| Placebo | Olfactory Dysfunction Outcomes Ratings (ODOR) Score Change | -7.5 score on a scale |
Comparison: The within-subject change in ODOR scores from baseline and 6 weeks was calculated for each individual patient. Then the median of all the patients' change in score for each cohort was calculated. Because these were within-subject changes in scores, the median difference values for each cohort do not necessarily correspond with simply subtracting the median change in score in the theophylline cohort from the median change in score in the placebo cohort. We confirmed the reported results.95% CI: [-2, 17]
Secondary
Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) Score Change
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.
Time frame: 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Theophylline | Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) Score Change | -6.5 score on a scale |
| Placebo | Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) Score Change | 1.5 score on a scale |
Comparison: The within-subject change in QOD-NS scores from baseline and 6 weeks was calculated for each individual patient. Then the median of all the patients' change in score for each cohort was calculated. Because these were within-subject changes in scores, the median difference values for each cohort do not necessarily correspond with simply subtracting the median change in score in the theophylline cohort from the median change in score in the placebo cohort.95% CI: [-15, -4]
Secondary
University of Pennsylvania Smell Identification Test (UPSIT) Total Score Change
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.
Time frame: 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Theophylline | University of Pennsylvania Smell Identification Test (UPSIT) Total Score Change | 1 score on a scale |
| Placebo | University of Pennsylvania Smell Identification Test (UPSIT) Total Score Change | 0 score on a scale |
95% CI: [-3, 5]