SCENT: Smell Changes & Efficacy of Nasal Theophylline

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT03990766
• Collaborator: (none)
• Enrollment: 27
• Location: 1
• Arms: 2
• Actual Duration (Months): 20.1
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Olfactory Disorder; Anosmia; Viral Infection; Theophylline Causing Adverse Effects in Therapeutic Use; Smell Disorder	Drug: Theophylline; Drug: Saline Nasal	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Two randomized armsTwo randomized arms
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double-blinded
• Primary Purpose: Treatment
• Official Title: SCENT Trial: Nasal Theophylline Irrigation for Treatment of Post-Viral Olfactory Dysfunction
• Actual Study Start Date: May 15, 2019
• Actual Primary Completion Date: Jan 15, 2021
• Actual Study Completion Date: Jan 15, 2021

Arms and Interventions

Arm	Intervention/Treatment
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; Theophylline delivered via high-volume, low-pressure nasal saline irrigation
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; Lactose delivered via high-volume, low-pressure nasal saline irrigation

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Improvement in Global Rating of Smell Change [6 weeks]

   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.

Secondary Outcome Measures

1. University of Pennsylvania Smell Identification Test (UPSIT) Total Score Change [6 weeks]

   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.

2. Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) Score Change [6 weeks]

   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.

3. Olfactory Dysfunction Outcomes Ratings (ODOR) Score Change [6 weeks]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: 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:

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University in St. Louis	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 18, 2019
• Informed Consent Form - Jan 15, 2021

More Information

Publications

None provided.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT03990766
• Other Study ID Numbers: 201901107
• First Posted: Jun 19, 2019
• Last Update Posted: Mar 31, 2022
• Last Verified: Mar 1, 2022

• 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.: No
• Keywords provided by Washington University School of Medicine: Olfactory dysfunction; Anosmia; Hyposmia; Post-viral; Theophylline; Adverse effects; Smell
• Additional relevant MeSH terms: Virus Diseases; Anosmia; Olfaction Disorders; Disease; Theophylline

Study Results

Participant Flow

Arm/Group Title	Theophylline	Placebo
Arm/Group Description	12 mg of theophylline dissolved in 240 mL of saline, administered to the bilateral nasal cavities twice a day for 6 weeks	Lactose capsule contents dissolved in 240 mL of saline, administered to the bilateral nasal cavities twice a day for 6 weeks
Period Title: Overall Study
STARTED	14	13
COMPLETED	12	10
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Theophylline Saline Irrigation	Placebo Saline Irrigation	Total
Arm/Group Description	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. Theophylline: Theophylline delivered via high-volume, low-pressure nasal 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. Saline Nasal: Lactose delivered via high-volume, low-pressure nasal saline irrigation	Total of all reporting groups
Overall Participants	12	10	22
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57.5	59.5	59.0
Sex: Female, Male (Count of Participants)
Female	8 66.7%	6 60%	14 63.6%
Male	4 33.3%	4 40%	8 36.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 8.3%	1 10%	2 9.1%
White	11 91.7%	9 90%	20 90.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	12 100%	10 100%	22 100%
Body Mass Index (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	32.3	33.0	33.0
Smoking history (Count of Participants)
Count of Participants [Participants]	0 0%	2 20%	2 9.1%
Deviated septum (Count of Participants)
Count of Participants [Participants]	3 25%	2 20%	5 22.7%
Diabetes mellitus (Count of Participants)
Count of Participants [Participants]	1 8.3%	1 10%	2 9.1%
Obstructive sleep apnea on positive airway pressure (Count of Participants)
Count of Participants [Participants]	2 16.7%	0 0%	2 9.1%
Hypothyroidism (Count of Participants)
Count of Participants [Participants]	3 25%	1 10%	4 18.2%
Family history of dementia (Count of Participants)
Count of Participants [Participants]	2 16.7%	1 10%	3 13.6%
Moderate/severe comorbidity (ACE-27 scores 2-3) (Count of Participants)
Count of Participants [Participants]	5 41.7%	1 10%	6 27.3%
Prior oral steroids (Count of Participants)
Count of Participants [Participants]	8 66.7%	6 60%	14 63.6%
Prior nasal steroids (Count of Participants)
Count of Participants [Participants]	9 75%	7 70%	16 72.7%
Prior olfactory training (Count of Participants)
Count of Participants [Participants]	1 8.3%	2 20%	3 13.6%
Time from upper respiratory infection to treatment (months) [Median (Full Range) ]
Median (Full Range) [months]	11.0	8.4	8.8

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Improvement in Global Rating of Smell Change
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Theophylline	Placebo
Arm/Group Description	12 mg of theophylline dissolved in 240 mL of saline, administered to the bilateral nasal cavities twice a day for 6 weeks	Lactose capsule contents dissolved in 240 mL of saline, administered to the bilateral nasal cavities twice a day for 6 weeks
Measure Participants	12	10
Count of Participants [Participants]	4 33.3%	3 30%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Theophylline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	3.3
	Confidence Interval	(2-Sided) 95%; -35.6 to 42.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	University of Pennsylvania Smell Identification Test (UPSIT) Total Score Change
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Theophylline	Placebo
Arm/Group Description	12 mg of theophylline dissolved in 240 mL of saline, administered to the bilateral nasal cavities twice a day for 6 weeks	Lactose capsule contents dissolved in 240 mL of saline, administered to the bilateral nasal cavities twice a day for 6 weeks
Measure Participants	12	10
Median (Full Range) [score on a scale]	1	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Theophylline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	1
	Confidence Interval	(2-Sided) 95%; -3 to 5
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) Score Change
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Theophylline	Placebo
Arm/Group Description	12 mg of theophylline dissolved in 240 mL of saline, administered to the bilateral nasal cavities twice a day for 6 weeks	Lactose capsule contents dissolved in 240 mL of saline, administered to the bilateral nasal cavities twice a day for 6 weeks
Measure Participants	12	10
Median (Full Range) [score on a scale]	-6.5	1.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Theophylline, Placebo
	Comments	The within-subject change in QOD-NS scores from baseline and 6 weeks was calculated for each individual patient. Then the median of all the patients' change in score for each cohort was calculated. Because these were within-subject changes in scores, the median difference values for each cohort do not necessarily correspond with simply subtracting the median change in score in the theophylline cohort from the median change in score in the placebo cohort.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-10
	Confidence Interval	(2-Sided) 95%; -15 to -4
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Olfactory Dysfunction Outcomes Ratings (ODOR) Score Change
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Theophylline	Placebo
Arm/Group Description	12 mg of theophylline dissolved in 240 mL of saline, administered to the bilateral nasal cavities twice a day for 6 weeks	Lactose capsule contents dissolved in 240 mL of saline, administered to the bilateral nasal cavities twice a day for 6 weeks
Measure Participants	12	10
Median (Full Range) [score on a scale]	-1.5	-7.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Theophylline, Placebo
	Comments	The within-subject change in ODOR scores from baseline and 6 weeks was calculated for each individual patient. Then the median of all the patients' change in score for each cohort was calculated. Because these were within-subject changes in scores, the median difference values for each cohort do not necessarily correspond with simply subtracting the median change in score in the theophylline cohort from the median change in score in the placebo cohort. We confirmed the reported results.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	7
	Confidence Interval	(2-Sided) 95%; -2 to 17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse event data were collected over 6 weeks of treatment
Adverse Event Reporting Description	The first 10 participants regardless of intervention underwent theophylline level measurements after 1 week of treatment. If a measurable amount of theophylline was identified, the test would be immediately repeated. If theophylline was detected in the second sample, the plan was to continue measuring in another 10 subjects. In addition, all participants were queried biweekly regarding any adverse effects.
Arm/Group Title	Theophylline		Placebo
Arm/Group Description	12 mg of theophylline dissolved in 240 mL of saline, administered to the bilateral nasal cavities twice a day for 6 weeks		Lactose capsule contents dissolved in 240 mL of saline, administered to the bilateral nasal cavities twice a day for 6 weeks
All Cause Mortality
	Theophylline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/13 (0%)
Serious Adverse Events
	Theophylline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Theophylline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/13 (0%)
Blood and lymphatic system disorders
Detectable serum theophylline	0/5 (0%)	0	0/5 (0%)	0

Limitations/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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.