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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Theophylline | Experimental | Participants will dissolve the contents of the 400 mg theophylline capsules (experimental) into the sinus rinse bottle containing nasal saline. |
|
| Placebo | Placebo Comparator | Participant will dissolve the contents of the identical-appearing lactose capsules (control) into the sinus rinse bottle containing nasal saline. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| theophylline | Drug | capsules dissolved in intranasal irrigation |
| |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | week 12 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Jay F Piccirillo, MD | Washington University School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University School of Medicine | St Louis | Missouri | 63110 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32340555 | Background | Kaye R, Chang CWD, Kazahaya K, Brereton J, Denneny JC 3rd. COVID-19 Anosmia Reporting Tool: Initial Findings. Otolaryngol Head Neck Surg. 2020 Jul;163(1):132-134. doi: 10.1177/0194599820922992. Epub 2020 Apr 28. | |
| 32563019 | Background | Meng X, Deng Y, Dai Z, Meng Z. COVID-19 and anosmia: A review based on up-to-date knowledge. Am J Otolaryngol. 2020 Sep-Oct;41(5):102581. doi: 10.1016/j.amjoto.2020.102581. Epub 2020 Jun 2. |
| Label | URL |
|---|---|
| Anosmia Rehabilitation in Patients Post Coronavirus Disease (COVID 19). | View source |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Theophylline | Participants will dissolve the contents of the 400 mg theophylline capsules (experimental) into the sinus rinse bottle containing nasal saline. theophylline: capsules dissolved in intranasal irrigation |
| FG001 | Placebo | Participant will dissolve the contents of the identical-appearing lactose capsules (control) into the sinus rinse bottle containing nasal saline. Placebo: identical-appearing lactose capsules dissolved in intranasal irrigation |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Theophylline | Participants will dissolve the contents of the 400 mg theophylline capsules (experimental) into the sinus rinse bottle containing nasal saline. theophylline: capsules dissolved in intranasal irrigation |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | Posted | Count of Participants | Participants | week 12 |
|
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.
Common systemic adverse effects of theophylline include headache, nausea, vomiting, tremors, insomnia, lightheadedness, and restlessness, while serious effects can include tachyarrhythmias, atrial fibrillation, Stevens-Johnson syndrome, intracranial hemorrhage, and seizure. However, intranasal theophylline has shown minimal adverse effects and negligible systemic absorption in prior studies.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Theophylline | Participants will dissolve the contents of the 400 mg theophylline capsules (experimental) into the sinus rinse bottle containing nasal saline. theophylline: capsules dissolved in intranasal irrigation |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| mid nose bleed | General disorders | Systematic Assessment |
The exact pathogenesis of COVID-related anosmia remains unclear, complicating targeted treatment development. Prior treatments like corticosteroids and olfactory training have shown limited or variable efficacy, and no gold standard exists.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dorina Kallogjeri, Assoc.Professor of Otolaryngology | Washington University, Department of Otolaryngology - Head and Neck Surgery | 314-362-1077 | kallgjerid@wustl.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 6, 2023 | May 19, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| D000086582 | Anosmia |
| D004408 | Dysgeusia |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D013806 | Theophylline |
| ID | Term |
|---|---|
| D014970 | Xanthines |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D011688 | Purinones |
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Single-site, double-blinded, placebo-controlled randomized clinical trial performed at a tertiary academic medical center.
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Double-blinded, meaning neither the subjects nor the investigators will be aware of the intervention received by any subject.
| Placebo |
| Drug |
identical-appearing lactose capsules dissolved in intranasal irrigation |
|
|
| 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. | 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. | 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. | up to 12 weeks |
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| 35797024 | Background | Gupta S, Lee JJ, Perrin A, Khan A, Smith HJ, Farrell N, Kallogjeri D, Piccirillo JF. Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for Treatment of COVID-19-Related Olfactory Dysfunction: The SCENT2 Phase 2 Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2022 Sep 1;148(9):830-837. doi: 10.1001/jamaoto.2022.1573. |
| 28653978 | Background | Dunlop BW, Gray J, Rapaport MH. Transdiagnostic Clinical Global Impression Scoring for Routine Clinical Settings. Behav Sci (Basel). 2017 Jun 27;7(3):40. doi: 10.3390/bs7030040. |
| 16267358 | Background | Barnes PJ. Theophylline in chronic obstructive pulmonary disease: new horizons. Proc Am Thorac Soc. 2005;2(4):334-9; discussion 340-1. doi: 10.1513/pats.200504-024SR. |
| 16859226 | Background | Tzelepis GE, Bascom AT, Safwan Badr M, Goshgarian HG. Effects of theophylline on pulmonary function in patients with traumatic tetraplegia. J Spinal Cord Med. 2006;29(3):227-33. doi: 10.1080/10790268.2006.11753878. |
| 30633180 | Background | Yu TJ, Liu YC, Chu CM, Hu HC, Kao KC. Effects of theophylline therapy on respiratory muscle strength in patients with prolonged mechanical ventilation: A retrospective cohort study. Medicine (Baltimore). 2019 Jan;98(2):e13982. doi: 10.1097/MD.0000000000013982. |
| 8497820 | Background | McKay SE, Howie CA, Thomson AH, Whiting B, Addis GJ. Value of theophylline treatment in patients handicapped by chronic obstructive lung disease. Thorax. 1993 Mar;48(3):227-32. doi: 10.1136/thx.48.3.227. |
| 35124402 | Background | Hosein W, Henkin RI. Therapeutic diminution of Interleukin-10 with intranasal theophylline administration in hyposmic patients. Am J Otolaryngol. 2022 Mar-Apr;43(2):103375. doi: 10.1016/j.amjoto.2022.103375. Epub 2022 Jan 28. |
| 34894449 | Background | Lee JJ, Peterson AM, Kallogjeri D, Jiramongkolchai P, Kukuljan S, Schneider JS, Klatt-Cromwell CN, Drescher AJ, Brunworth JD, Piccirillo JF. Smell Changes and Efficacy of Nasal Theophylline (SCENT) irrigation: A randomized controlled trial for treatment of post-viral olfactory dysfunction. Am J Otolaryngol. 2022 Mar-Apr;43(2):103299. doi: 10.1016/j.amjoto.2021.103299. Epub 2021 Dec 3. |
| 35797023 | Background | Lee JJ, Gupta S, Kallogjeri D, Piccirillo JF. Safety of High-Dose Nasal Theophylline Irrigation in the Treatment of Postviral Olfactory Dysfunction: A Dose-Escalation Study. JAMA Otolaryngol Head Neck Surg. 2022 Sep 1;148(9):885-886. doi: 10.1001/jamaoto.2022.1574. |
| 6463130 | Background | Doty RL, Shaman P, Dann M. Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiol Behav. 1984 Mar;32(3):489-502. doi: 10.1016/0031-9384(84)90269-5. |
| Background | Theophylline in Dextrose [package insert]. Lake Forest, IL: Hospira, INC;2008 |
| COVID-19 Anosmia Study. | View source |
| Corticosteroid Nasal Spray in COVID-19 Anosmia. | View source |
Participant will dissolve the contents of the identical-appearing lactose capsules (control) into the sinus rinse bottle containing nasal saline.
Placebo: identical-appearing lactose capsules dissolved in intranasal irrigation
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Parosmia | Count of Participants | Participants |
|
| Phantosmia | Count of Participants | Participants |
|
| The University of Pennsylvania Smell Identification Test | The University of Pennsylvania Smell Identification Test (UPSIT) is a clinically validated, 40-question forced-choice odor identification test used to objectively assess olfactory function. UPSIT scores help determine the presence and severity of olfactory dysfunction, with specific cutoff values indicating decreased olfactory function (≤34 for women, ≤33 for men). Higher scores indicate better olfactory function, and lower scores reflect greater olfactory dysfunction. | Median | Full Range | score on a scale (0-40) |
|
| The Olfactory Dysfunction Outcomes Rating | The The Olfactory Dysfunction Outcomes Rating (ODOR) scale consists of 28 questions, each addressing a specific aspect of how olfactory dysfunction impacts a person's life. Each question is typically answered on a Likert scale, ranging from 0 (no difficulty or very rarely bothered) to 4 (complete difficulty or very frequently bothered). The scores for all 28 items are summed to obtain a total score, which can range from 0 to 112 points. | Median | Full Range | score on a scale 0-112 |
|
| Clinical Global Impression of Severity of Smell Loss | Count of Participants | Participants |
|
| Theophylline |
Participants will dissolve the contents of the 400 mg theophylline capsules (experimental) into the sinus rinse bottle containing nasal saline. theophylline: capsules dissolved in intranasal irrigation |
| OG001 | Placebo | Participant will dissolve the contents of the identical-appearing lactose capsules (control) into the sinus rinse bottle containing nasal saline. Placebo: identical-appearing lactose capsules dissolved in intranasal irrigation |
|
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| Secondary | 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. | Posted | Mean | 95% Confidence Interval | score on a scale (0-112) | 6 weeks and 12 week |
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| Secondary | 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. | Posted | Number | participants | 12 weeks |
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| Secondary | 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. | Posted | Count of Participants | Participants | within first 3 weeks |
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| Secondary | 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. | Posted | Number | participants | up to 12 weeks |
|
|
|
| 0 |
| 39 |
| 0 |
| 39 |
| 4 |
| 39 |
| EG001 | Placebo | Participant will dissolve the contents of the identical-appearing lactose capsules (control) into the sinus rinse bottle containing nasal saline. Placebo: identical-appearing lactose capsules dissolved in intranasal irrigation | 0 | 38 | 0 | 38 | 8 | 38 |
| Dry nose noted and blood tingled nasal discharge | General disorders | Systematic Assessment |
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| Small amount of epistaxis and cold during the first week | General disorders | Systematic Assessment |
|
| Upper respiratory of infection and sleep disturbing cough | General disorders | Systematic Assessment |
|
| Little hard red bumps inside and outside of nose | General disorders | Systematic Assessment |
|
| Migraine | General disorders | Systematic Assessment |
|
| Participants developed a sinus infection | General disorders | Systematic Assessment |
|
| Patient developed nausea, vomiting and diarrhea | General disorders | Systematic Assessment |
|
| Nasal soreness | General disorders | Systematic Assessment |
|
| Urine in blood | General disorders | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D000857 | Olfaction Disorders |
| D012678 | Sensation Disorders |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D013651 | Taste Disorders |
| D011687 |
| Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| 10 days |
|
| 11 days |
|
| 12 days |
|
| 13 days |
|
| 14 days |
|
| Small amount of epistaxis and cold during the first week. |
|
| Upper respiratory infection and sleep disturbing cough |
|
| Little hard red bumps inside and outside of nose. |
|
| Migraine |
|
| Participant developed a sinus infection |
|
| Patient developed nausea, vomiting, and diarrhea |
|
| Nasal soreness |
|
| Urine in blood |
|