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CompletedNCT03990766SCENTUpdated Mar 31, 2022Results posted

Smell Changes & Efficacy of Nasal Theophylline

A Phase 2 interventional study of Theophylline and Saline Nasal in Olfactory Disorder, Anosmia and Viral Infection, sponsored by Washington University School of Medicine. Completed at 1 site in United States. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2022-03-31.

Sponsored by Washington University School of Medicine · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
27
Allocation
Randomized
Ages
18 Years to 70 Years
Sex
All
01

Study summary

This study evaluates the efficacy and safety of nasal theophylline irrigation in treating smell loss related to a viral respiratory infection. Half the participants will undergo nasal theophylline irrigation treatment while the other half will undergo placebo nasal irrigation with saline alone. All participants will have their sense of smell tested before and after 6 weeks of treatment. All participants will also be regularly asked about any potential side effects related to treatment. In addition, the first 10 participants will have their blood drawn to measure their theophylline level after 1 week of starting treatment to ensure it is not abnormally elevated.

02

Conditions studied

  • Olfactory Disorder
  • Anosmia
  • Viral Infection
  • Theophylline Causing Adverse Effects in Therapeutic Use
  • Smell Disorder

Keywords

  • Olfactory dysfunction
  • Anosmia
  • Hyposmia
  • Post-viral
  • Theophylline
  • Adverse effects
  • Smell
03

Who can participate

Ages eligible
18 Years to 70 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Subjective or clinically diagnosed olfactory dysfunction of 6 months to 36 months duration after a presumed viral upper respiratory infection
  • Ability to read, write, and understand English

Exclusion criteria

Exclusion Criteria:

  • Dependence on theophylline for comorbid conditions such as asthma and chronic obstructive pulmonary disease
  • History of an allergic reaction to theophylline or other methylxanthines
  • Prior sinonasal or anterior skull base surgery
  • Nasal polyposis
  • 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 (≥40%) interactions with theophylline, which include cimetidine, ciprofloxacin, disulfiram, enoxacin, fluvoxamine, interferon-alpha, lithium, mexiletine, phenytoin, propafenone, propranolol, tacrine, thiabendazole, ticlopidine, and troleandomycin
04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
27 participants (actual)

Study arms

  • Experimental
    Theophylline saline irrigation

    Theophylline 12 mg capsule contents dissolved into a sinus rinse bottle containing distilled or boiled tap water and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture commercially prepared packets, delivered to the bilateral nasal cavities twice daily.

    Drug: Theophylline

  • Placebo comparator
    Placebo saline irrigation

    Identical-appearing lactose monohydrate capsule contents dissolved into a sinus rinse bottle containing distilled or boiled tap water and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture commercially prepared packets, delivered to the bilateral nasal cavities twice daily.

    Drug: Saline Nasal

Interventions

  • DrugTheophylline

    Theophylline delivered via high-volume, low-pressure nasal saline irrigation

  • DrugSaline Nasal

    Lactose delivered via high-volume, low-pressure nasal saline irrigation

05

What researchers measure

Primary outcomes

  1. Number of Patients With Improvement in Global Rating of Smell Change

    Self-reported change in smell after intervention on a 7-point Likert scale. Response options with corresponding point values: 7) Much better, 6) Somewhat better, 5) Slightly better, 4) Neither better nor worse, 3) Slightly worse, 2) Somewhat worse, and 1) Much worse. The maximum score is 7, and higher values indicate better outcomes. A score of 4 is considered neutral. Scores of 5 or higher indicated clinical improvement.

    Time frame: 6 weeks

Secondary outcomes

  1. University of Pennsylvania Smell Identification Test (UPSIT) Total Score Change

    Within- and between-subject changes in UPSIT total scores measured at baseline and at 6 weeks after therapy. This test is a validated 40-question forced-choice odor identification test where microencapsulated odorants on a strip are released by scratching. Each question corresponds to one point, and there are no subscales. The minimum score is 0 while the maximum score is 40, and higher values indicate better outcomes.

    Time frame: 6 weeks

  2. Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) Score Change

    Within- and between-subject changes in QOD-NS scores measured at baseline and at 6 weeks after therapy, which is a validated 17-item questionnaire about quality of life and impairments related to olfactory dysfunction. Each question is scored from 0 to 3 points, and there are no subscales. The minimum score is 0 while the maximum score is 51, and higher values indicate worse quality of life or higher degree of impairment.

    Time frame: 6 weeks

  3. Olfactory Dysfunction Outcomes Ratings (ODOR) Score Change

    Within- and between-subject changes measured at baseline and at 6 weeks after therapy. This test is a new disease-specific 28-item questionnaire that assesses for physical, functional, and emotional limitations in patients with olfactory dysfunction of any etiology. Each question is scored from 0 to 4. The minimum score is 0 while the maximum score is 112, and higher values indicate higher degree of limitations and worse outcomes. There are no subscales within the current questionnaire.

    Time frame: 6 weeks

06

Results

Posted Mar 31, 2022
Limitations and caveats
The diagnosis of PVOD is by patient history and is thus subject to recall bias. In addition, PVOD treatment response may differ according to the causative virus, which is rarely known. The sample size was limited since all non-life saving clinical research and recruitment were halted at our institution at the time due to COVID-19. Lastly, the optimal dosing of theophylline irrigations is yet to be determined.

Participant flow

Participant flow — Overall Study
MilestoneTheophyllinePlacebo
Started1413
Completed1210
Not completed23

Outcome measures

PrimaryNumber of Patients With Improvement in Global Rating of Smell Change

Self-reported change in smell after intervention on a 7-point Likert scale. Response options with corresponding point values: 7) Much better, 6) Somewhat better, 5) Slightly better, 4) Neither better nor worse, 3) Slightly worse, 2) Somewhat worse, and 1) Much worse. The maximum score is 7, and higher values indicate better outcomes. A score of 4 is considered neutral. Scores of 5 or higher indicated clinical improvement.

Time frame:
6 weeks
Reported as:
Count of participants · Participants
Number of Patients With Improvement in Global Rating of Smell Change
ParticipantsTheophyllinePlacebo
Number of Patients With Improvement in Global Rating of Smell Change43
Statistical analysis
  • Theophylline vs Placebo · Risk difference (rd): 3.3 · 95% CI -35.6 to 42.3
SecondaryUniversity of Pennsylvania Smell Identification Test (UPSIT) Total Score Change

Within- and between-subject changes in UPSIT total scores measured at baseline and at 6 weeks after therapy. This test is a validated 40-question forced-choice odor identification test where microencapsulated odorants on a strip are released by scratching. Each question corresponds to one point, and there are no subscales. The minimum score is 0 while the maximum score is 40, and higher values indicate better outcomes.

Time frame:
6 weeks
Reported as:
Median · score on a scale
University of Pennsylvania Smell Identification Test (UPSIT) Total Score Change
score on a scaleTheophyllinePlacebo
University of Pennsylvania Smell Identification Test (UPSIT) Total Score Change1 (-4 to 12)0 (-8 to 5)
Statistical analysis
  • Theophylline vs Placebo · Median difference (net): 1 · 95% CI -3 to 5
SecondaryQuestionnaire of Olfactory Disorders-Negative Statements (QOD-NS) Score Change

Within- and between-subject changes in QOD-NS scores measured at baseline and at 6 weeks after therapy, which is a validated 17-item questionnaire about quality of life and impairments related to olfactory dysfunction. Each question is scored from 0 to 3 points, and there are no subscales. The minimum score is 0 while the maximum score is 51, and higher values indicate worse quality of life or higher degree of impairment.

Time frame:
6 weeks
Reported as:
Median · score on a scale
Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) Score Change
score on a scaleTheophyllinePlacebo
Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) Score Change-6.5 (-15 to 4)1.5 (-4 to 19)
Statistical analysis
  • Theophylline vs Placebo · Median difference (net): -10 · 95% CI -15 to -4
SecondaryOlfactory Dysfunction Outcomes Ratings (ODOR) Score Change

Within- and between-subject changes measured at baseline and at 6 weeks after therapy. This test is a new disease-specific 28-item questionnaire that assesses for physical, functional, and emotional limitations in patients with olfactory dysfunction of any etiology. Each question is scored from 0 to 4. The minimum score is 0 while the maximum score is 112, and higher values indicate higher degree of limitations and worse outcomes. There are no subscales within the current questionnaire.

Time frame:
6 weeks
Reported as:
Median · score on a scale
Olfactory Dysfunction Outcomes Ratings (ODOR) Score Change
score on a scaleTheophyllinePlacebo
Olfactory Dysfunction Outcomes Ratings (ODOR) Score Change-1.5 (-18 to 6)-7.5 (-29 to 6)
Statistical analysis
  • Theophylline vs Placebo · Median difference (net): 7 · 95% CI -2 to 17

Adverse events

Collected over Adverse event data were collected over 6 weeks of treatment. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Theophylline0/14 (0%)0/14 (0%)0/14 (0%)
Placebo0/13 (0%)0/13 (0%)0/13 (0%)
Most frequent other events
Most frequent other events
EventTheophyllinePlacebo
Detectable serum theophyllineBlood and lymphatic system disorders0/50/5

Baseline characteristics

Age, Continuous
Age, Continuous(years)Theophylline Saline IrrigationPlacebo Saline IrrigationTotal
Median57.5 (40 to 70)59.5 (32 to 67)59.0 (32 to 70)
Sex: Female, Male
Sex: Female, Male(Participants)Theophylline Saline IrrigationPlacebo Saline IrrigationTotal
Female8614
Male448
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Theophylline Saline IrrigationPlacebo Saline IrrigationTotal
American Indian or Alaska Native000
Asian000
Native Hawaiian or Other Pacific Islander000
Black or African American112
White11920
More than one race000
Unknown or Not Reported000
Region of Enrollment
Region of Enrollment(participants)Theophylline Saline IrrigationPlacebo Saline IrrigationTotal
United States121022
Body Mass Index
Body Mass Index(kg/m^2)Theophylline Saline IrrigationPlacebo Saline IrrigationTotal
Median32.3 (21.6 to 49.5)33.0 (22.7 to 45.6)33.0 (21.6 to 49.5)
Smoking history
Smoking history(Participants)Theophylline Saline IrrigationPlacebo Saline IrrigationTotal
Count of participants022
Deviated septum
Deviated septum(Participants)Theophylline Saline IrrigationPlacebo Saline IrrigationTotal
Count of participants325
Diabetes mellitus
Diabetes mellitus(Participants)Theophylline Saline IrrigationPlacebo Saline IrrigationTotal
Count of participants112

8 further baseline measures are reported on the registry.

07

Study locations

1 site
  • Washington University in St. Louis
    Saint Louis, Missouri 63110, United States
08

References and documents

Study documents

  • Protocol and statistical analysis plan · Apr 18, 2019
  • Informed consent form · Jan 15, 2021

Documents are hosted by the registry — open the source record to download them.

09

Registry details

Key details

Study ID
NCT03990766
Lead sponsor
Washington University School of Medicine
Responsible party
Sponsor
First posted
Jun 19, 2019
Start date
May 15, 2019
Primary completion
Jan 15, 2021
Completion
Jan 15, 2021
Results posted
Mar 31, 2022
Last update
Mar 31, 2022

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
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