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Smell in Covid-19 and Efficacy of Nasal Theophylline (SCENT2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04789499
Recruitment Status : Completed
First Posted : March 9, 2021
Last Update Posted : February 3, 2022
Sponsor:
Information provided by (Responsible Party):
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.


Condition or disease Intervention/treatment Phase
Covid19 Anosmia Olfactory Disorder Covid-19 Pandemic SARS-CoV-2 Infection Hyposmia Ageusia Hypogeusia Drug: Theophylline Powder Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 62 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description: The pharmacy will maintain the blind until the completion of the study.
Primary Purpose: Treatment
Official Title: Smell in Covid-19 and Efficacy of Nasal Theophylline
Actual Study Start Date : March 15, 2021
Actual Primary Completion Date : December 30, 2021
Actual Study Completion Date : December 30, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Theophylline
400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily.
Drug: 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.


Placebo Comparator: Placebo
500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily.
Drug: 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.





Primary Outcome Measures :
  1. Clinical Global Impression Scale [ Time Frame: Comparison at 6 weeks post-intervention from baseline ]
    The response rate defined as the number of participants self reporting minimal change or larger in the Clinical Global Impression Scale (CGI) scale, divided by the number of participants in each group. The CGI has two components - the CGI-Severity and the CGI-Improvement. The CGI-Severity Scale from 1-7 (1 is Normal, 7 is Complete loss of smell) provides subjective data on the patient's perceived severity of their dysfunction at baseline. The CGI-Improvement Scale from 1-7 (1 is Very Much Improved, 7 is Very Much Worsened) measures changes at 3 weeks and post-treatment at 6 weeks. 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 number of responders to non-responders will be compared between the two arms.


Secondary Outcome Measures :
  1. University of Pennsylvania Smell Identification Test (UPSIT) [ Time Frame: Comparison at 6 weeks post-intervention from baseline ]
    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.

  2. Questionnaire for Olfactory Dysfunction (QOD) [ Time Frame: Comparison at 6 weeks post-intervention from baseline ]
    This test will measure changes in the health-related quality of life of participants based on four factors as outlined by Mattos, et al. This will qualify which factor (eating, mental health, social interactions, or fear of dysfunction) was affected most by the proposed intervention. The survey also includes questions on parosmia, a phenomena of COVID-related OD.

  3. 36-Item Short Form Health Survey (SF-36) [ Time Frame: 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.

  4. Olfactory Dysfunction Outcomes Rating (ODOR) [ Time Frame: Comparison at 6 weeks post-intervention from baseline ]
    ODOR is a new disease-specific questionnaire that assesses for physical, functional, and emotional limitations in participants with olfactory dysfunction of any etiology. Based on the recurring impairments for participants with post-viral OD in eating/appetite, environmental safety, interpersonal relationships, hygiene, and mood, 28 items were generated to create the new patient reported outcome measure.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04789499


Locations
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United States, Missouri
Washington University School of Medicine in Saint Louis
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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Principal Investigator: Jay F Piccirillo, M.D., FACS Washington University School of Medicine
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT04789499    
Other Study ID Numbers: 202101190
First Posted: March 9, 2021    Key Record Dates
Last Update Posted: February 3, 2022
Last Verified: February 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Washington University School of Medicine:
Smell
Smell loss
smell dysfunction
olfactory dysfunction
COVID-19
anosmia
theophylline
nasal irrigation
Additional relevant MeSH terms:
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COVID-19
Anosmia
Ageusia
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Olfaction Disorders
Sensation Disorders
Neurologic Manifestations
Nervous System Diseases
Taste Disorders
Theophylline
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents