A Phase 2 interventional study of theophylline and Placebo in COVID-19, sponsored by Washington University School of Medicine. Completed at 1 site in United States. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2025-08-20.
Sponsored by Washington University School of Medicine · Phase 2, Interventional, and Treatment
The purpose of this Phase II trial is to test the effectiveness of intranasal theophylline irrigations for the treatment of COVID-19 related smell dysfunction. The investigators will compare the effect of theophylline nasal rinses versus placebo nasal rinses on smell symptoms. Participants will be asked to rinse their nose with a medication or placebo capsule dissolved in saltwater twice daily for 12 weeks and fill out surveys about smell before, during, and at the end of treatment.
This study will also be used to describe adverse effects related to intranasal theophylline irrigation.
COVID-related olfactory dysfunction (OD) is a major symptom of infection with SARS-COV-2, affecting up to 80% of those with COVID-19. While research on the pathogenesis is ongoing, a significant subset is expected to suffer from long-term OD. The investigators seek to test intranasal theophylline nasal irrigation as a potential therapeutic option for treatment of COVID-related OD lasting over 3 months.
Theophylline has been shown to improve outcomes in post-viral OD in pilot studies, and initial data suggests therapeutic benefit in patients with post-COVID OD with minimal systemic absorption.
The primary hypothesis is that theophylline irrigation will be more effective than placebo saline irrigation for COVID-19 related OD symptoms. The use of intranasal theophylline will have minimal adverse effects.
Participants will be recruited based on the following inclusion criteria:
Exclusion Criteria:
Individuals will not be allowed to participate in this study if they meet one or more of the following exclusion criteria:
Participants will dissolve the contents of the 400 mg theophylline capsules (experimental) into the sinus rinse bottle containing nasal saline.
Drug: theophylline
Participant will dissolve the contents of the identical-appearing lactose capsules (control) into the sinus rinse bottle containing nasal saline.
Drug: Placebo
capsules dissolved in intranasal irrigation
identical-appearing lactose capsules dissolved in intranasal irrigation
Also known as: inactive medicine
Clinical Global Impression - Improvement Scale
The Clinical Global Impression-Improvement scale (CGI-I) is a subjective rating scale used to measure changes in a patient's condition over time. It ranges from 1 to 7, where 1 means "Very Much Improved," 2 means "Much Improved," 3 means "Minimally Improved," 4 means "No Change," 5 means "Minimally Worse," 6 means "Much Worse," and 7 means "Very Much Worsened." In this study, participants reporting scores of 1, 2, or 3 on the CGI-I are considered responders to treatment. The primary analysis will compare the proportion of responders between the theophylline and placebo groups assessing both within-subject changes over time and between-group differences. We will measure 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 main comparison will be focused on changes at 12-weeks
Time frame: week 12
Olfactory Dysfunction Outcomes Rating
Olfactory Dysfunction Outcomes Rating (ODOR) is a disease-specific questionnaire that assesses for physical, functional, and emotional limitations in participants with olfactory dysfunction of any etiology. The instrument contains 28 total items with each scored on a 5-point Likert scale from 0 to 4. Total score ranges from 0 to 112. Higher scores indicate higher degree of dysfunction and limitation.
Time frame: 6 weeks and 12 week
Assessment of Adherence
Participants will be contacted to report the number of irrigations completed over the prior 7 days out of a possible 14. Participants report their compliance with the twice-daily nasal irrigations through self-reported measures in REDCap surveys, including how many rinses they have completed. The measure count represents the self-reported compliance with twice daily irrigations.
Time frame: 12 weeks
Assessment of Blind
The assessment of the blind in this study involves contacting participants within the first 3 weeks after starting nasal irrigations and asking them which treatment arm they believe they were assigned to-either "theophylline and nasal saline irrigation" or "nasal saline irrigation alone." The numbers reported represent how many participants correctly guessed an arm in which they were assigned to.
Time frame: within first 3 weeks
Adverse Effects
Patients will be asked to report any adverse effects they experience at any time during the 12-week study period. An adverse event in this study refers to any undesirable or unintended medical occurrence experienced by a participant during the trial, which may or may not be related to the use of intranasal theophylline.
Time frame: up to 12 weeks
Per protocol the study plans to enroll 240 patients to account for a 20% dropout rate, aiming to have 200 evaluable participants for the trial. Reported are 77 randomized patients.
| Milestone | Theophylline | Placebo |
|---|---|---|
| Started | 39 | 38 |
| Completed | 21 | 27 |
| Not completed | 18 | 11 |
The Clinical Global Impression-Improvement scale (CGI-I) is a subjective rating scale used to measure changes in a patient's condition over time. It ranges from 1 to 7, where 1 means "Very Much Improved," 2 means "Much Improved," 3 means "Minimally Improved," 4 means "No Change," 5 means "Minimally Worse," 6 means "Much Worse," and 7 means "Very Much Worsened." In this study, participants reporting scores of 1, 2, or 3 on the CGI-I are considered responders to treatment. The primary analysis will compare the proportion of responders between the theophylline and placebo groups assessing both within-subject changes over time and between-group differences. We will measure 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 main comparison will be focused on changes at 12-weeks
| Participants | Theophylline | Placebo |
|---|---|---|
| Clinical Global Impression - Improvement Scale | 9 | 9 |
Olfactory Dysfunction Outcomes Rating (ODOR) is a disease-specific questionnaire that assesses for physical, functional, and emotional limitations in participants with olfactory dysfunction of any etiology. The instrument contains 28 total items with each scored on a 5-point Likert scale from 0 to 4. Total score ranges from 0 to 112. Higher scores indicate higher degree of dysfunction and limitation.
| score on a scale (0-112) | Theophylline | Placebo |
|---|---|---|
| 6 weeks | 43.38 (34.35 to 52.41) | 45.96 (38.21 to 53.72) |
| 12 weeks | 43.94 (35.08 to 52.80) | 45.26 (37.33 to 53.18) |
Participants will be contacted to report the number of irrigations completed over the prior 7 days out of a possible 14. Participants report their compliance with the twice-daily nasal irrigations through self-reported measures in REDCap surveys, including how many rinses they have completed. The measure count represents the self-reported compliance with twice daily irrigations.
| participants | Theophylline | Placebo |
|---|---|---|
| 6 days | 1 | 1 |
| 8 days | 1 | 0 |
| 10 days | 1 | 1 |
| 11 days | 1 | 0 |
| 12 days | 5 | 1 |
| 13 days | 2 | 4 |
| 14 days | 18 | 25 |
The assessment of the blind in this study involves contacting participants within the first 3 weeks after starting nasal irrigations and asking them which treatment arm they believe they were assigned to-either "theophylline and nasal saline irrigation" or "nasal saline irrigation alone." The numbers reported represent how many participants correctly guessed an arm in which they were assigned to.
| Participants | Theophylline | Placebo |
|---|---|---|
| Assessment of Blind | 20 | 26 |
Patients will be asked to report any adverse effects they experience at any time during the 12-week study period. An adverse event in this study refers to any undesirable or unintended medical occurrence experienced by a participant during the trial, which may or may not be related to the use of intranasal theophylline.
| participants | Theophylline | Placebo |
|---|---|---|
| Mild nose bleed | 1 | 0 |
| Dry nose noted and blood-tinged nasal discharge | 1 | 0 |
| Small amount of epistaxis and cold during the first week. | 1 | 0 |
| Upper respiratory infection and sleep disturbing cough | 1 | 0 |
| Little hard red bumps inside and outside of nose. | 0 | 1 |
| Migraine | 0 | 1 |
| Participant developed a sinus infection | 0 | 3 |
| Patient developed nausea, vomiting, and diarrhea | 0 | 1 |
| Nasal soreness | 0 | 1 |
| Urine in blood | 0 | 1 |
Collected over Adverse event data will be collected throughout the entire 12-week study period. Specifically, participants will be asked about adverse events during phone check-ins at weeks 3, 6, 9, and 12. Additionally, participants can report adverse events at any time by contacting the study team via phone or pager, who are available 24/7 during the trial.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Theophylline | 0/39 (0%) | 0/39 (0%) | 4/39 (10.3%) |
| Placebo | 0/38 (0%) | 0/38 (0%) | 8/38 (21.1%) |
| Event | Theophylline | Placebo |
|---|---|---|
| Participants developed a sinus infectionGeneral disorders | 0/39 | 3/38 |
| Little hard red bumps inside and outside of noseGeneral disorders | 0/39 | 1/38 |
| MigraineGeneral disorders | 0/39 | 1/38 |
| Patient developed nausea, vomiting and diarrheaGeneral disorders | 0/39 | 1/38 |
| Nasal sorenessGeneral disorders | 0/39 | 1/38 |
| Urine in bloodGeneral disorders | 0/39 | 1/38 |
| mid nose bleedGeneral disorders | 1/39 | 0/38 |
| Dry nose noted and blood tingled nasal dischargeGeneral disorders | 1/39 | 0/38 |
| Small amount of epistaxis and cold during the first weekGeneral disorders | 1/39 | 0/38 |
| Upper respiratory of infection and sleep disturbing coughGeneral disorders | 1/39 | 0/38 |
| Age, Continuous(years) | Theophylline | Placebo | Total |
|---|---|---|---|
| Mean | 47 ± 14 | 49 ± 13 | 48 ± 13 |
| Sex: Female, Male(Participants) | Theophylline | Placebo | Total |
|---|---|---|---|
| Female | 30 | 26 | 56 |
| Male | 9 | 12 | 21 |
| Race/Ethnicity, Customized(Participants) | Theophylline | Placebo | Total |
|---|---|---|---|
| American Indian or Alaskan Native | 0 | 1 | 1 |
| Asian | 0 | 0 | 0 |
| Black or African American | 2 | 0 | 2 |
| Hispanic or Latino | 1 | 0 | 1 |
| Native Hawaiian or pacific Islander | 0 | 0 | 0 |
| White | 18 | 25 | 43 |
| Asian and White | 0 | 1 | 1 |
| Parosmia(Participants) | Theophylline | Placebo | Total |
|---|---|---|---|
| Yes | 28 | 29 | 57 |
| No | 11 | 9 | 20 |
| Phantosmia(Participants) | Theophylline | Placebo | Total |
|---|---|---|---|
| Yes | 17 | 17 | 34 |
| No | 22 | 21 | 43 |
| The University of Pennsylvania Smell Identification Test(score on a scale (0-40)) | Theophylline | Placebo | Total |
|---|---|---|---|
| Median | 25 (5 to 34) | 28 (7 to 34) | 25 (5 to 34) |
| The Olfactory Dysfunction Outcomes Rating(score on a scale 0-112) | Theophylline | Placebo | Total |
|---|---|---|---|
| Median | 52 (0 to 105) | 47 (14 to 89) | 49 (0 to 105) |
| Clinical Global Impression of Severity of Smell Loss(Participants) | Theophylline | Placebo | Total |
|---|---|---|---|
| Absent | 7 | 6 | 13 |
| Poor | 25 | 21 | 46 |
| Fair | 5 | 9 | 14 |
| Good | 0 | 1 | 1 |
| Very Good | 0 | 1 | 1 |
| Excellent | 2 | 0 | 2 |
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Washington University School of Medicine