Ageusia, Anosmia, Covid19, Covid-19 Pandemic, Hypogeusia, Hyposmia, Olfactory Disorder, SARS-CoV-2 Infection
Conditions
Keywords
Smell, Smell loss, smell dysfunction, olfactory dysfunction, COVID-19, anosmia, theophylline, nasal irrigation
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.
Interventions
DRUGTheophylline Powder
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.
DRUGPlacebo Comparator
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.
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
The pharmacy will maintain the blind until the completion of the study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Olfactory dysfunction that has persisted for \>3 months following suspected COVID-19 infection * Residing within the states of Missouri or Illinois. * Can read, write, and understand English.
Exclusion criteria
* History of olfactory dysfunction prior to COVID-19 infection * Use of concomitant therapies specifically for the treatment of olfactory dysfunction * History of olfactory dysfunction longer than 12 months * Known existence of nasal polyps, prior sinonasal, or anterior skull-based surgery * Dependence on theophylline for comorbid conditions such as asthma and COPD * History of an allergic reaction to theophylline or other methylxanthines * 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 interactions with theophylline, which include cimetidine, ciprofloxacin, disulfiram, enoxacin, fluvoxamine, interferon-alpha, lithium, mexiletine, phenytoin, propafenone, propranolol, tacrine, thiabendazole, ticlopidine, and troleandomycin. * Pre-existing arrhythmias or seizures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| UPSIT | Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups | UPSIT 0-40 with higher scores indicating better results. The response rate defined as the number of participants in each group self-reporting of at least slightly better improvement in the Clinical Global Improvement Scale at 6 weeks post intervention as compared to baseline, devided by the total number of participants in that specific group. The CGI-Improvement Scale has seven response options (from 1 as Very Much Improved to 7 as Very Much Worsened) for answers to the question Compared to your sense of smell before you started the nasal irrigations, how would you rate your sense of smell now . 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 rate of responders will be compared between the two arms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| University of Pennsylvania Smell Identification Test (UPSIT) | Comparison at 6 weeks post-intervention from baseline | UPSIT 0-40 with higher scores indicating better smell. This test is an objective, 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 symptoms. |
| Change in Questionnaire for Olfactory Dysfunction (QOD) From Baseline to 6 Weeks Post Intervention | Comparison at 6 weeks post-intervention from baseline | Questionnaire for Olfactory Dysfunction (QOD) assesses health-related quality of life of participants based on four factors such as eating, mental health, social interactions, or fear of dysfunction.. The survey also includes questions on parosmia, a phenomena of COVID-related OD. The QOD consists of 17 statements that participants score from 0-3, resulting in a total score from 0 to 51. Higher scores reflect better olfactory-specific QOL. |
| 36-Item Short Form Health Survey (SF-36) | Baseline assessment | 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. This test allows us to study the overall quality of life for those suffering from COVID-19 related OD. There is no single overall score for SF-36. The SF 36 generates 8 subscales with scores ranging from 0 (worst) to 100 (best). General health domain scores are reported here. |
| Olfactory Dysfunction Outcomes Rating (ODOR) | Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups | The ODOR is a 28-item QOL instrument with a total score ranging from 0 to 112 points. Higher scores indicate worse QOL with higher degree of dysfunction and limitation. A decrease of 15 or more points is deemed to be a clinically significant improvement in QOL. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Theophylline 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily.
Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. 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 it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally.
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. | 26 |
| Placebo 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily.
Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. 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 it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally.
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. | 25 |
| Total | 51 |
Baseline characteristics
| Characteristic | Placebo | Total | Theophylline |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 4 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 47 Participants | 25 Participants |
| Age, Continuous | 47.08 years STANDARD_DEVIATION 13.89 | 45.96 years STANDARD_DEVIATION 13.11 | 42.43 years STANDARD_DEVIATION 11.63 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 25 participants | 51 participants | 26 participants |
| Sex: Female, Male Female | 17 Participants | 36 Participants | 19 Participants |
| Sex: Female, Male Male | 8 Participants | 15 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 25 |
| other Total, other adverse events | 7 / 26 | 11 / 25 |
| serious Total, serious adverse events | 0 / 26 | 0 / 25 |
Outcome results
Primary
UPSIT
UPSIT 0-40 with higher scores indicating better results. The response rate defined as the number of participants in each group self-reporting of at least slightly better improvement in the Clinical Global Improvement Scale at 6 weeks post intervention as compared to baseline, devided by the total number of participants in that specific group. The CGI-Improvement Scale has seven response options (from 1 as Very Much Improved to 7 as Very Much Worsened) for answers to the question Compared to your sense of smell before you started the nasal irrigations, how would you rate your sense of smell now . 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 rate of responders will be compared between the two arms.
Time frame: Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups
Population: This outcome measure could be assessed only from the participants that completed CGI-I at 6 weeks post intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Theophylline | UPSIT | 59 percentage of participants |
| Placebo | UPSIT | 43 percentage of participants |
Secondary
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. This test allows us to study the overall quality of life for those suffering from COVID-19 related OD. There is no single overall score for SF-36. The SF 36 generates 8 subscales with scores ranging from 0 (worst) to 100 (best). General health domain scores are reported here.
Time frame: Baseline assessment
Population: This was a baseline assessment only, so all randomized participants are analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Theophylline | 36-Item Short Form Health Survey (SF-36) | 75 score on a scale |
| Placebo | 36-Item Short Form Health Survey (SF-36) | 80 score on a scale |
Secondary
Change in Questionnaire for Olfactory Dysfunction (QOD) From Baseline to 6 Weeks Post Intervention
Questionnaire for Olfactory Dysfunction (QOD) assesses health-related quality of life of participants based on four factors such as eating, mental health, social interactions, or fear of dysfunction.. The survey also includes questions on parosmia, a phenomena of COVID-related OD. The QOD consists of 17 statements that participants score from 0-3, resulting in a total score from 0 to 51. Higher scores reflect better olfactory-specific QOL.
Time frame: Comparison at 6 weeks post-intervention from baseline
Population: Since the outcome is measuring the change in QOD, only the data from participant completing QOD at baseline and 6 weeks were included
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Theophylline | Change in Questionnaire for Olfactory Dysfunction (QOD) From Baseline to 6 Weeks Post Intervention | 0.86 score on a scale |
| Placebo | Change in Questionnaire for Olfactory Dysfunction (QOD) From Baseline to 6 Weeks Post Intervention | 1.43 score on a scale |
Secondary
Olfactory Dysfunction Outcomes Rating (ODOR)
The ODOR is a 28-item QOL instrument with a total score ranging from 0 to 112 points. Higher scores indicate worse QOL with higher degree of dysfunction and limitation. A decrease of 15 or more points is deemed to be a clinically significant improvement in QOL.
Time frame: Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups
Population: This outcome is assessed only for participants that have ODOR assessed at baseline and at 6 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Theophylline | Olfactory Dysfunction Outcomes Rating (ODOR) | -6.5 score on a scale |
| Placebo | Olfactory Dysfunction Outcomes Rating (ODOR) | -4.5 score on a scale |
Secondary
University of Pennsylvania Smell Identification Test (UPSIT)
UPSIT 0-40 with higher scores indicating better smell. This test is an objective, 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 symptoms.
Time frame: Comparison at 6 weeks post-intervention from baseline
Population: The outcome measure could be assessed only on subjects that completed UPSIT test at 6 weeks post-intervention
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Theophylline | University of Pennsylvania Smell Identification Test (UPSIT) | 3 score on a scale |
| Placebo | University of Pennsylvania Smell Identification Test (UPSIT) | 0 score on a scale |