Anosmia, Covid19
Conditions
Keywords
Novel Coronavirus, Anosmia, Smell Loss, Parosmia, Fish Oil Supplement, Omega-3 Fatty Acid Supplements
Brief summary
To capture the natural history of COVID-19 associated olfactory dysfunction as measured by two patient reported outcome measures (SNOT-22, QOD-NS) and a 6-week BSIT with a comparison to an intervention arm receiving daily omega-3 supplements.
Detailed description
Infection with the novel coronavirus (COVID-19) has been linked to new-onset olfactory dysfunction, often as the only presenting symptom. In one multicenter European study, 85.6% of patients with mild to moderate symptoms reported hyposmia or anosmia with early recovery of olfactory function in just under half of patients. However, the pathogenesis and natural history of COVID-19 related olfactory dysfunction is poorly understood. Anosmia most commonly arises in association with sinonasal disease or post-infectious or post-traumatic disorders. Notably, olfactory loss has been associated with impaired quality of life, higher rates of depression, and even increased mortality risk. Spontaneous recovery has been observed in patients with post- infectious olfactory dysfunction, typically over a period of months to years, with an estimated one-third of patients demonstrating meaningful improvement after one year. Smell retraining therapy appears to be an effective therapeutic option for patients with post-infectious olfactory dysfunction, particularly for patients who initiate treatment within one year from onset of symptoms, but requires an intervention period of at least three to four months. Various pharmacotherapies have been investigated in the treatment of post-infectious anosmia but none have clearly demonstrated utility with the exception of a possible benefit for nasal steroid irrigations in combination with smell retraining therapy. More recently, omega-3 polyunsaturated fat supplementation has emerged as a promising pharmacotherapy for olfactory dysfunction in patients without sinonasal disease. Omega-3 fatty acid deficient mice demonstrate evidence of olfactory dysfunction and mice receiving omega-3 fatty acids have improved recovery after peripheral nerve injury, which has been linked to neuroprotective effects mediated through anti-oxidant and anti-inflammatory pathways. In humans, a large cross-sectional study found that older adults with higher dietary fat intake had lower incidence of olfactory impairment. From a clinical perspective, patients without sinonasal disease receiving postoperative omega-3 fatty acid supplementation after endoscopic endonasal skull base surgery in a randomized control trial demonstrated a significantly greater rate of return of normal olfactory dysfunction. Little is known about either the natural history of olfactory dysfunction associated with COVID-19 infection or about the therapeutic efficacy of omega-3 fatty acid supplementation in patients with post-viral anosmia. The study team hopes to gain a better understanding of each through a randomized double-blind placebo control study that assesses both objective and subjective perception of olfactory dysfunction over a period of 6 weeks after infection.
Interventions
Participants randomized to this arm will be instructed to take two of the softgels they received per day for 6 weeks. They will receive softgels containing 1,000 mg of omega-3 fatty acid. 1000 mg of omega-3 fatty acid blend including 683 mg Eicosapentaenoic Acid and 252 mg Docosahexaenoic Acid
DRUGPlacebo/Control
Patients randomized to this arm will also be instructed to take two of the softgels they received per day for 6 weeks. They will receive placebo softgels that are indistinguishable from those containing fish oil.
Sponsors
Icahn School of Medicine at Mount Sinai
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
The healthcare providers interacting with the patients, as well as the participants themselves, will not know which arm they have been assigned to. Only the research fellows will have access to the randomization scheme.
Intervention model description
Patients will be randomized into treatment and control groups. The treatment group will receive omega-3-fatty acid supplementation (1000 mg of omega-3 fatty acid blend including 683 mg Eicosapentaenoic Acid and 252 mg Docosahexaenoic Acid) to be taken twice daily for 6 weeks. The control arm will receive a placebo pill to be taken twice daily.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults (18 years of age or older) with self-reported new-onset olfactory dysfunction * Positive COVID-19 diagnosis will be deemed eligible for inclusion.
Exclusion criteria
* Patients \<18 years of age * Patients who are unable to provide informed consent * Patients without a positive COVID-19 PCR result obtained through nasopharyngeal swab - Patients with a COVID-19 diagnosis but without self-reported anosmia * Patients with severe COVID-19 disease as defined by the Mouth Sinai Health System Treatment Guidelines for SARS-COV-2 (requiring high flow nasal cannula, non-rebreather, CPAP/BIPAP, or mechanical ventilation OR patients requiring pressor medication OR patients with evidence of end organ damage) * Patients with pre-existing self-reported olfactory dysfunction * Patients with a history of chronic nasal/sinus infections (rhinosinusitis) or history of endoscopic sinus surgery * Patients using nasal steroid sprays or irrigations for any reason * Patients who are prisoners of the state * Patients who have psychiatric or developmental disorder conditions that may impair ability to provide informed consent * Patients will also be excluded if they have an allergy to fish or an omega-3 supplement, or do not eat fish or fish- containing substances for any reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Brief Smell Identification Test (BSIT) | Week 0 and Week 6 | Change in BSIT. Brief Smell Identification Test (BSIT) is a 12-item instrument, full range score from 0 to 12, higher score indicates better olfactory performances. |
| Change in Brief Smell Identification Test (BSIT) in Participants With Severe Olfactory Dysfunction | Week 0 and Week 6 | Mean change in BSIT in participants with severe olfactory dysfunction defined as BSIT ≤ 7. Brief Smell Identification Test (BSIT) is a 12-item instrument, full range score from 0 to 12, higher score indicates better olfactory performances. |
| Change in Brief Smell Identification Test (BSIT) in Participants With Laboratory-Confirmed COVID-19 and Severe Olfactory Dysfunction | Week 0 and Week 6 | Mean change in BSIT in participants with laboratory-confirmed COVID-19. Brief Smell Identification Test (BSIT) is a 12-item instrument, full range score from 0 to 12, higher score indicates better olfactory performances. |
| Change in Brief Smell Identification Test (BSIT) in Participants With Laboratory-Confirmed COVID-19 | Week 0 and Week 6 | Mean change in BSIT in participants with severe olfactory dysfunction defined as BSIT ≤ 6. Brief Smell Identification Test (BSIT) is a 12-item instrument, full range score from 0 to 12, higher score indicates better olfactory performances. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS) | baseline, weeks 1, 2, 4 and 6 after softgel initiation | The modified Brief Questionnaire of Olfactory Dysfunction - Negative Statements (QOD-NS) survey is a 17-item instrument, each item graded on a scale from 0 to 3, with total scale range from 0 to 51. Higher score indicates better olfactory-specific quality of life (QOL). |
| Sinonasal Outcomes Test (SNOT-22) | baseline, weeks 1, 2, 4 and 6 after softgel initiation | Sino-Nasal Outcome Test (SNOT-22) is a 22-item instrument, total scale range from 0 to 110, higher score indicates more severe QOL impact. |
Countries
United States
Participant flow
Recruitment details
Participants with laboratory-confirmed or clinically-suspected COVID-19 infection and self-reported new-onset OD from August 2020 to November 2021 were prospectively recruited from otolaryngology and primary care practices across a large metropolitan health system as well as through a web-based symptom-tracking application and self-referral, resulting in a cohort of individuals from throughout the United States.
Participants by arm
| Arm | Count |
|---|---|
| Omega-3 2,000mg daily of O3FA supplementation in the form of 2 capsules of Nature Made® Ultra Omega-3 Fish Oil 1400mg, each of which contains 1000 mg of O3FAs | 57 |
| Placebo/Control received a placebo pill of identical size and shape to be taken twice daily. | 60 |
| Total | 117 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 10 | 4 |
| Overall Study | Withdrawal by Subject | 3 | 5 |
Baseline characteristics
| Characteristic | Omega-3 | Placebo/Control | Total |
|---|---|---|---|
| Age, Continuous | 41.5 years STANDARD_DEVIATION 14.6 | 40.7 years STANDARD_DEVIATION 12.7 | 41.1 years STANDARD_DEVIATION 13.6 |
| Anosmia Severity (Current) | 68.1 units on a scale STANDARD_DEVIATION 27.7 | 73.2 units on a scale STANDARD_DEVIATION 22.2 | 70.8 units on a scale STANDARD_DEVIATION 25 |
| Anosmia Severity (Worst) | 91.9 units on a scale STANDARD_DEVIATION 16.9 | 96.0 units on a scale STANDARD_DEVIATION 8.54 | 93.9 units on a scale STANDARD_DEVIATION 13.3 |
| Comorbidities, n (%) Ageusia | 41 Participants | 48 Participants | 89 Participants |
| Comorbidities, n (%) Allergic Rhinitis | 3 Participants | 6 Participants | 9 Participants |
| Comorbidities, n (%) Chronic Rhinosinusitis | 1 Participants | 1 Participants | 2 Participants |
| Comorbidities, n (%) History of Facial Trauma | 2 Participants | 0 Participants | 2 Participants |
| Comorbidities, n (%) Neurodegenerative Disease | 1 Participants | 0 Participants | 1 Participants |
| Concomitant Therapies Used During the Trial, n (%) *** Intranasal Corticosteroid Spray or Irrigation | 6 Participants | 7 Participants | 13 Participants |
| Concomitant Therapies Used During the Trial, n (%) *** Nasal Saline | 5 Participants | 8 Participants | 13 Participants |
| Concomitant Therapies Used During the Trial, n (%) *** Oral Corticosteroids | 5 Participants | 3 Participants | 8 Participants |
| Concomitant Therapies Used During the Trial, n (%) *** Smell Training | 12 Participants | 17 Participants | 29 Participants |
| Duration of Olfactory Dysfunction Prior to Trial Start | 196 days STANDARD_DEVIATION 105 | 204 days STANDARD_DEVIATION 95.6 | 200 days STANDARD_DEVIATION 99.6 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 46 Participants | 46 Participants | 92 Participants |
| Sex: Female, Male Male | 11 Participants | 14 Participants | 25 Participants |
| Therapies Used Prior to Trial Start Intranasal Corticosteroid Spray or Irrigation | 5 Participants | 5 Participants | 10 Participants |
| Therapies Used Prior to Trial Start Nasal Saline Spray or Irrigation | 11 Participants | 11 Participants | 22 Participants |
| Therapies Used Prior to Trial Start Oral Corticosteroids | 0 Participants | 3 Participants | 3 Participants |
| Therapies Used Prior to Trial Start Other | 3 Participants | 8 Participants | 11 Participants |
| Therapies Used Prior to Trial Start Smell Training | 24 Participants | 24 Participants | 48 Participants |
| Type of Olfactory Dysfunction Anosmia | 45 Participants | 47 Participants | 92 Participants |
| Type of Olfactory Dysfunction Hyposmia | 4 Participants | 6 Participants | 10 Participants |
| Type of Olfactory Dysfunction Hyposmia & Parosmia | 7 Participants | 7 Participants | 14 Participants |
| Type of Olfactory Dysfunction Parosmia | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 70 | 0 / 69 |
| other Total, other adverse events | 0 / 70 | 5 / 69 |
| serious Total, serious adverse events | 0 / 70 | 0 / 69 |
Outcome results
Primary
Change in Brief Smell Identification Test (BSIT)
Change in BSIT. Brief Smell Identification Test (BSIT) is a 12-item instrument, full range score from 0 to 12, higher score indicates better olfactory performances.
Time frame: Week 0 and Week 6
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Omega-3 | Change in Brief Smell Identification Test (BSIT) | Baseline | 6.77 score on a scale | Standard Deviation 1.94 |
| Omega-3 | Change in Brief Smell Identification Test (BSIT) | Week 6 | 7.89 score on a scale | Standard Deviation 2 |
| Omega-3 | Change in Brief Smell Identification Test (BSIT) | Change | 1.12 score on a scale | Standard Deviation 1.99 |
| Placebo/Control | Change in Brief Smell Identification Test (BSIT) | Baseline | 7.20 score on a scale | Standard Deviation 1.88 |
| Placebo/Control | Change in Brief Smell Identification Test (BSIT) | Week 6 | 7.88 score on a scale | Standard Deviation 2.19 |
| Placebo/Control | Change in Brief Smell Identification Test (BSIT) | Change | 0.68 score on a scale | Standard Deviation 1.86 |
Primary
Change in Brief Smell Identification Test (BSIT) in Participants With Laboratory-Confirmed COVID-19
Mean change in BSIT in participants with severe olfactory dysfunction defined as BSIT ≤ 6. Brief Smell Identification Test (BSIT) is a 12-item instrument, full range score from 0 to 12, higher score indicates better olfactory performances.
Time frame: Week 0 and Week 6
Population: Data not collected
Primary
Change in Brief Smell Identification Test (BSIT) in Participants With Laboratory-Confirmed COVID-19 and Severe Olfactory Dysfunction
Mean change in BSIT in participants with laboratory-confirmed COVID-19. Brief Smell Identification Test (BSIT) is a 12-item instrument, full range score from 0 to 12, higher score indicates better olfactory performances.
Time frame: Week 0 and Week 6
Population: Participants with Laboratory-Confirmed COVID-19
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omega-3 | Change in Brief Smell Identification Test (BSIT) in Participants With Laboratory-Confirmed COVID-19 and Severe Olfactory Dysfunction | 1.18 score on a scale | Standard Deviation 1.88 |
| Placebo/Control | Change in Brief Smell Identification Test (BSIT) in Participants With Laboratory-Confirmed COVID-19 and Severe Olfactory Dysfunction | 0.61 score on a scale | Standard Deviation 1.87 |
Primary
Change in Brief Smell Identification Test (BSIT) in Participants With Severe Olfactory Dysfunction
Mean change in BSIT in participants with severe olfactory dysfunction defined as BSIT ≤ 7. Brief Smell Identification Test (BSIT) is a 12-item instrument, full range score from 0 to 12, higher score indicates better olfactory performances.
Time frame: Week 0 and Week 6
Population: Participants with severe olfactory dysfunction defined as BSIT ≤ 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omega-3 | Change in Brief Smell Identification Test (BSIT) in Participants With Severe Olfactory Dysfunction | 2.30 score on a scale | Standard Deviation 1.77 |
| Placebo/Control | Change in Brief Smell Identification Test (BSIT) in Participants With Severe Olfactory Dysfunction | 1.63 score on a scale | Standard Deviation 1.82 |
Secondary
Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS)
The modified Brief Questionnaire of Olfactory Dysfunction - Negative Statements (QOD-NS) survey is a 17-item instrument, each item graded on a scale from 0 to 3, with total scale range from 0 to 51. Higher score indicates better olfactory-specific quality of life (QOL).
Time frame: baseline, weeks 1, 2, 4 and 6 after softgel initiation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Omega-3 | Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS) | week 1 | 11.41 score on a scale | Standard Deviation 4.42 |
| Omega-3 | Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS) | week 4 | 11.17 score on a scale | Standard Deviation 5.15 |
| Omega-3 | Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS) | week 2 | 11.46 score on a scale | Standard Deviation 4.81 |
| Omega-3 | Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS) | week 6 | 11.19 score on a scale | Standard Deviation 4.58 |
| Omega-3 | Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS) | baseline | 12.29 score on a scale | Standard Deviation 4.46 |
| Placebo/Control | Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS) | week 6 | 12.33 score on a scale | Standard Deviation 4.8 |
| Placebo/Control | Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS) | baseline | 13.73 score on a scale | Standard Deviation 4.33 |
| Placebo/Control | Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS) | week 1 | 12.54 score on a scale | Standard Deviation 4.83 |
| Placebo/Control | Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS) | week 2 | 12.76 score on a scale | Standard Deviation 4.41 |
| Placebo/Control | Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS) | week 4 | 12.95 score on a scale | Standard Deviation 4.67 |
Secondary
Sinonasal Outcomes Test (SNOT-22)
Sino-Nasal Outcome Test (SNOT-22) is a 22-item instrument, total scale range from 0 to 110, higher score indicates more severe QOL impact.
Time frame: baseline, weeks 1, 2, 4 and 6 after softgel initiation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Omega-3 | Sinonasal Outcomes Test (SNOT-22) | baseline | 22.35 score on a scale | Standard Deviation 13.23 |
| Omega-3 | Sinonasal Outcomes Test (SNOT-22) | week 4 | 20.79 score on a scale | Standard Deviation 13.56 |
| Omega-3 | Sinonasal Outcomes Test (SNOT-22) | week 1 | 21.23 score on a scale | Standard Deviation 13.6 |
| Omega-3 | Sinonasal Outcomes Test (SNOT-22) | week 6 | 19.91 score on a scale | Standard Deviation 13.05 |
| Omega-3 | Sinonasal Outcomes Test (SNOT-22) | week 2 | 21.41 score on a scale | Standard Deviation 14.33 |
| Placebo/Control | Sinonasal Outcomes Test (SNOT-22) | week 6 | 22.41 score on a scale | Standard Deviation 13.58 |
| Placebo/Control | Sinonasal Outcomes Test (SNOT-22) | week 2 | 22.90 score on a scale | Standard Deviation 12.58 |
| Placebo/Control | Sinonasal Outcomes Test (SNOT-22) | baseline | 25.75 score on a scale | Standard Deviation 12.43 |
| Placebo/Control | Sinonasal Outcomes Test (SNOT-22) | week 1 | 24.54 score on a scale | Standard Deviation 12.9 |
| Placebo/Control | Sinonasal Outcomes Test (SNOT-22) | week 4 | 23.47 score on a scale | Standard Deviation 13.82 |