COVID-19
Conditions
Keywords
Nasal Theophylline, Olfactory disfunction, Anosmia, Gustatory disorders, Dysgeusia
Brief summary
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.
Detailed description
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.
Interventions
DRUGtheophylline
capsules dissolved in intranasal irrigation
DRUGPlacebo
identical-appearing lactose capsules dissolved in intranasal irrigation
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Double-blinded, meaning neither the subjects nor the investigators will be aware of the intervention received by any subject.
Intervention model description
Single-site, double-blinded, placebo-controlled randomized clinical trial performed at a tertiary academic medical center.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Participants will be recruited based on the following inclusion criteria: 1. males and females ages 18 to 75 years 2. located within or willing to travel to the state of Missouri or Illinois 3. Olfactory dysfunction that has persisted for \>3 months following suspected COVID-19 infection 4. Baseline University of Pennsylvania Smell Identification Test (UPSIT) consistent with decreased olfactory function (\<= 34 in women, \<=33 in men). This test is a clinically validated 40-question forced-choice odor identification test where microencapsulated odorants on a strip are released by scratching.70 This will determine that patients have both subjectively and objectively diagnosed OD prior to undergoing treatment. 5. Ability to read, write, and understand English and have access to email.
Exclusion criteria
* Individuals will not be allowed to participate in this study if they meet one or more of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression - Improvement Scale | week 12 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Olfactory Dysfunction Outcomes Rating | 6 weeks and 12 week | 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. |
| Assessment of Adherence | 12 weeks | 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. |
| Assessment of Blind | within first 3 weeks | 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. |
| Adverse Effects | up to 12 weeks | 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. |
Countries
United States
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 39 |
| 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 | 38 |
| Total | 77 |
Baseline characteristics
| Characteristic | Theophylline | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 47 years STANDARD_DEVIATION 14 | 49 years STANDARD_DEVIATION 13 | 48 years STANDARD_DEVIATION 13 |
| Clinical Global Impression of Severity of Smell Loss Absent | 7 Participants | 6 Participants | 13 Participants |
| Clinical Global Impression of Severity of Smell Loss Excellent | 2 Participants | 0 Participants | 2 Participants |
| Clinical Global Impression of Severity of Smell Loss Fair | 5 Participants | 9 Participants | 14 Participants |
| Clinical Global Impression of Severity of Smell Loss Good | 0 Participants | 1 Participants | 1 Participants |
| Clinical Global Impression of Severity of Smell Loss Poor | 25 Participants | 21 Participants | 46 Participants |
| Clinical Global Impression of Severity of Smell Loss Very Good | 0 Participants | 1 Participants | 1 Participants |
| Parosmia No | 11 Participants | 9 Participants | 20 Participants |
| Parosmia Yes | 28 Participants | 29 Participants | 57 Participants |
| Phantosmia No | 22 Participants | 21 Participants | 43 Participants |
| Phantosmia Yes | 17 Participants | 17 Participants | 34 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian and White | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 18 Participants | 25 Participants | 43 Participants |
| Sex: Female, Male Female | 30 Participants | 26 Participants | 56 Participants |
| Sex: Female, Male Male | 9 Participants | 12 Participants | 21 Participants |
| The Olfactory Dysfunction Outcomes Rating | 52 score on a scale 0-112 | 47 score on a scale 0-112 | 49 score on a scale 0-112 |
| The University of Pennsylvania Smell Identification Test | 25 score on a scale (0-40) | 28 score on a scale (0-40) | 25 score on a scale (0-40) |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 39 | 0 / 38 |
| other Total, other adverse events | 4 / 39 | 8 / 38 |
| serious Total, serious adverse events | 0 / 39 | 0 / 38 |
Outcome results
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
Time frame: week 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Theophylline | Clinical Global Impression - Improvement Scale | 9 Participants |
| Placebo | Clinical Global Impression - Improvement Scale | 9 Participants |
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.
Time frame: up to 12 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Theophylline | Adverse Effects | Mild nose bleed | 1 participants |
| Theophylline | Adverse Effects | Dry nose noted and blood-tinged nasal discharge | 1 participants |
| Theophylline | Adverse Effects | Small amount of epistaxis and cold during the first week. | 1 participants |
| Theophylline | Adverse Effects | Upper respiratory infection and sleep disturbing cough | 1 participants |
| Theophylline | Adverse Effects | Little hard red bumps inside and outside of nose. | 0 participants |
| Theophylline | Adverse Effects | Migraine | 0 participants |
| Theophylline | Adverse Effects | Participant developed a sinus infection | 0 participants |
| Theophylline | Adverse Effects | Patient developed nausea, vomiting, and diarrhea | 0 participants |
| Theophylline | Adverse Effects | Nasal soreness | 0 participants |
| Theophylline | Adverse Effects | Urine in blood | 0 participants |
| Placebo | Adverse Effects | Patient developed nausea, vomiting, and diarrhea | 1 participants |
| Placebo | Adverse Effects | Mild nose bleed | 0 participants |
| Placebo | Adverse Effects | Migraine | 1 participants |
| Placebo | Adverse Effects | Dry nose noted and blood-tinged nasal discharge | 0 participants |
| Placebo | Adverse Effects | Urine in blood | 1 participants |
| Placebo | Adverse Effects | Small amount of epistaxis and cold during the first week. | 0 participants |
| Placebo | Adverse Effects | Participant developed a sinus infection | 3 participants |
| Placebo | Adverse Effects | Upper respiratory infection and sleep disturbing cough | 0 participants |
| Placebo | Adverse Effects | Nasal soreness | 1 participants |
| Placebo | Adverse Effects | Little hard red bumps inside and outside of nose. | 1 participants |
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.
Time frame: 12 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Theophylline | Assessment of Adherence | 10 days | 1 participants |
| Theophylline | Assessment of Adherence | 12 days | 5 participants |
| Theophylline | Assessment of Adherence | 8 days | 1 participants |
| Theophylline | Assessment of Adherence | 13 days | 2 participants |
| Theophylline | Assessment of Adherence | 11 days | 1 participants |
| Theophylline | Assessment of Adherence | 14 days | 18 participants |
| Theophylline | Assessment of Adherence | 6 days | 1 participants |
| Placebo | Assessment of Adherence | 14 days | 25 participants |
| Placebo | Assessment of Adherence | 6 days | 1 participants |
| Placebo | Assessment of Adherence | 8 days | 0 participants |
| Placebo | Assessment of Adherence | 10 days | 1 participants |
| Placebo | Assessment of Adherence | 11 days | 0 participants |
| Placebo | Assessment of Adherence | 12 days | 1 participants |
| Placebo | Assessment of Adherence | 13 days | 4 participants |
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.
Time frame: within first 3 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Theophylline | Assessment of Blind | 20 Participants |
| Placebo | Assessment of Blind | 26 Participants |
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.
Time frame: 6 weeks and 12 week
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Theophylline | Olfactory Dysfunction Outcomes Rating | 6 weeks | 43.38 score on a scale (0-112) |
| Theophylline | Olfactory Dysfunction Outcomes Rating | 12 weeks | 43.94 score on a scale (0-112) |
| Placebo | Olfactory Dysfunction Outcomes Rating | 6 weeks | 45.96 score on a scale (0-112) |
| Placebo | Olfactory Dysfunction Outcomes Rating | 12 weeks | 45.26 score on a scale (0-112) |