Smell in Covid-19 and Efficacy of Nasal Theophylline

Study Overview
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Brief Summary
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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
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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.

Official Title
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Smell in Covid-19 and Efficacy of Nasal Theophylline

Conditions
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Covid19, Anosmia, Olfactory Disorder, Covid-19 Pandemic, SARS-CoV-2 Infection, Hyposmia, Ageusia, Hypogeusia

Intervention / Treatment
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* Drug: Theophylline Powder
* Drug: Placebo Comparator


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Theophylline<br>400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily for six weeks. | Drug: Theophylline Powder<br>* 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.<br>* Other names: Theophylline nasal irrigation;|
| Placebo Comparator: Placebo<br>500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily for six weeks. | Drug: Placebo Comparator<br>* 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.<br>* Other names: lactose powder;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Comparison at 6 weeks post-intervention from baseline | 
| 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. | Comparison at 6 weeks post-intervention from baseline | 
| 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. | Baseline assessment | 
| 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. | Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Smell, Smell loss, smell dysfunction, olfactory dysfunction, COVID-19, anosmia, theophylline, nasal irrigation