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

April 27, 2023 updated by: Washington University School of Medicine

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

51

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Washington University School of Medicine in Saint Louis

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 68 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Theophylline
400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily for six weeks.
Drug: Theophylline 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.
Other Names:
  • Theophylline nasal irrigation
Placebo Comparator: Placebo
500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily for six weeks.
Drug: Placebo 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.
Other Names:
  • lactose powder

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
UPSIT
Time Frame: 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.
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)
Time Frame: 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.
Comparison at 6 weeks post-intervention from baseline
Change in Questionnaire for Olfactory Dysfunction (QOD) From Baseline to 6 Weeks Post Intervention
Time Frame: 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.
Comparison at 6 weeks post-intervention from baseline
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. 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)
Time Frame: 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.
Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Washington University School of Medicine

Investigators

  • Principal Investigator: Jay F Piccirillo, M.D., FACS, Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 15, 2021

Primary Completion (Actual)

December 30, 2021

Study Completion (Actual)

December 30, 2021

Study Registration Dates

First Submitted

March 8, 2021

First Submitted That Met QC Criteria

March 8, 2021

First Posted (Actual)

March 9, 2021

Study Record Updates

Last Update Posted (Actual)

May 24, 2023

Last Update Submitted That Met QC Criteria

April 27, 2023

Last Verified

April 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 202101190

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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