Smell in Covid-19 and Efficacy of Nasal Theophylline

Phase 2

Completed

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

Interventions: Drug: Theophylline Powder
Drug: Placebo Comparator

Registration Number: NCT04789499

Lead Sponsor: Washington University School of Medicine

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 51

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Theophylline	Theophylline Powder	400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily for six weeks.
Placebo	Placebo Comparator	500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily for six weeks.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.