Cognitive Impairment, Post-COVID-19 Condition, Post-COVID-19 Syndrome
Conditions
Keywords
vortioxetine, fatigue, long COVID, post-acute COVID syndrome PASC, long haul COVID, brain fog, cognitive deficit, cognitive dysfunction, COVID-19 sequelae, post-acute COVID-19 syndrome, Trintellix, chronic COVID syndrome, post-COVID-19 condition, long hauler, anti-inflammatory, persistent COVID-19
Brief summary
A randomized, double-blinded, placebo-controlled trial will be conducted to evaluate vortioxetine, an antidepressant with established pro-cognitive properties, for the treatment of cognitive deficits which develop during or after an infection consistent with COVID-19, continue for 2+ months, and are not explained by an alternative diagnosis (i.e., post-COVID-19 condition). Participants (aged 18-64 years) will receive vortioxetine (10-20 mg) or placebo for 8 weeks. Participants 65+ years will receive vortioxetine (5-10 mg) or placebo for 8 weeks. Changes in cognitive functioning from baseline to endpoint (week 8) will be assessed via the Digit Symbol Substitution Test (DSST). Study visits may be conducted remotely (e.g. via Zoom, by telephone), and/or in-person.
Detailed description
A significant percentage of individuals who have recovered from acute COVID-19 infection present with unabating, non-specific, distressing, and functionally impairing symptoms (i.e., post-COVID-19 condition). Commonly reported symptoms include, but are not limited to, cognitive impairment (e.g., brain fog), fatigue, apathy, depression, anxiety, insomnia, anergia, and loss of appetite. Toward the aim of identifying a common nomenclature and case definition, the World Health Organization (WHO) has recently proposed the moniker 'post COVID-19 condition'. It is estimated that approximately 10-30% of persons infected with COVID-19 experience characteristic symptoms persisting for more than 12 weeks following documentation of positive COVID-19 diagnosis. Consensus exists that the phenomenology of post-COVID-19 condition is subserved by disturbance in immune-inflammatory systems. Currently, no treatment is identified as safe and effective for post-COVID-19 condition. A candidate treatment for post-COVID-19 condition should be capable of improving measures of cognitive function (i.e., objective and subjective), motivation and energy, as well as reducing fatigue. The rationale for prioritizing cognition as a primary therapeutic target is based on a concatenation of study results reporting that cognitive complaints/deficits and fatigue are some of the most common and debilitating features of post-COVID-19 condition. Preliminary evidence suggests that some antidepressants (e.g., SSRIs) are capable of reducing respiratory complications secondary to COVID-19 via putative mechanisms including, but not limited to, sigma-1 agonism and acid sphingomyelinase. Vortioxetine is established as pro-cognitive, as evidenced by significant improvement on both subjective and objective measures. Vortioxetine is also documented to improve anticipatory and consummatory measures of reward function/anhedonia, improve general functioning, and measures of motivation and energy. Moreover, vortioxetine is not associated with emotional blunting and has preliminary evidence of improving sleep behaviour and circadian rhythms. The candidacy of vortioxetine as an effective treatment for post-COVID-19 condition is also strengthened by evidence indicating that vortioxetine exerts modulatory effects on cellular and cytokine systems known to be activated in persons with post-COVID-19 condition. Herein, we hypothesize that vortioxetine will be more effective than placebo in the treatment of cognitive impairment in persons with post-COVID-19 condition.
Interventions
DRUGVortioxetine
Participants aged 18-64 years receiving vortioxetine will be provided 10 mg/day on days 1-14 of the treatment period, and will be titrated to 20 mg/day at the start of week 3 (day 15) based on study clinician judgment. For the remaining 6 weeks, the dose of vortioxetine will be 20 mg/day, unless adjudicated otherwise by a study clinician. Per product monograph, participants aged 65+ years receiving vortioxetine will be provided 5 mg/day on days 1-14 of the treatment period, and will be titrated to 10 mg/day at the start of week 3 (day 15) based on study clinician judgment. For the remaining 6 weeks, the dose of vortioxetine will be 10 mg/day, unless adjudicated otherwise by a study clinician.
DRUGPlacebo
A placebo pill will be taken once daily.
Sponsors
Brain and Cognition Discovery Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18+ * Meets WHO-defined post-COVID-19 condition (WHO definition: 'Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others\* and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.') To ensure the above criteria is met, participants will only be included in the study if they meet all eligibility criteria more than 12 weeks from the onset of their acute Covid-19 symptoms or positive PCR/antigen test. * Documented history of SARS-CoV-2 infection (positive PCR/antigen test during acute illness OR clinical diagnosis by physician during or after the acute illness). * Subjective cognitive complaints as detected by the Perceived Deficits Questionnaire (PDQ)-5. * Ability to provide written informed consent. * Resident of Canada.
Exclusion criteria
* Current symptoms are fully explained by major depressive disorder or bipolar disorder. * Pre-existing conditions that may cause cognitive impairment, or symptoms similar to those seen in post-COVID-19 condition (e.g., major neurocognitive disorder, schizophrenia, chronic fatigue syndrome \[CFS\]/ encephalitis meningitis \[EM\]), as assessed by Mini International Neuropsychiatric Interview (MINI) 7.0.2. * Inability to follow study procedures. * Known intolerance to vortioxetine and/or prior trial of vortioxetine with demonstrated inefficacy. * If participants are currently taking other antidepressants, they will be asked to discontinue the antidepressant for 2-4 weeks in order to participate in the study. * Patients on other antidepressants are allowed to participate only if the antidepressant is prescribed at subtherapeutic doses for a primary indication other than mood disorders. Participants will be made aware in the consent form that the combination of the two antidepressants would be considered investigational and that the safety/efficacy profiles are unknown. * Current alcohol or substance use disorder. * Inability to provide consent. * Current alcohol and/or substance use disorder as confirmed by the M.I.N.I 7.0.2. * Presence of comorbid psychiatric disorder that is a primary focus of clinical concern as confirmed by the M.I.N.I. 7.0.2. * Medications approved and/or employed off-label for cognitive dysfunction (e.g., psychostimulants). * Any medication for a general medical disorder that, in the opinion of the investigator, may affect cognitive function. * Use of benzodiazepines within 12 hours of cognitive assessments. * Consumption of alcohol within 8 hours of cognitive assessments. * Physical, cognitive, or language impairments sufficient to adversely affect data derived from cognitive assessments. * Diagnosed reading disability or dyslexia. * Clinically significant learning disorder by history. * Electroconvulsive therapy (ECT) in the last 6 months. * History of moderate or severe head trauma (e.g., loss of consciousness for \>1 hour), other neurological disorders, or unstable systemic medical diseases that in the opinion of the investigator are likely to affect the central nervous system. * Pregnant and/or breastfeeding. * Received investigational agents as part of a separate study within 30 days of the screening visit. * Actively suicidal/presence of suicidal ideation or evaluated as being at suicide risk (as per clinical judgment). * Currently receiving treatment with Monoamine Oxidase Inhibitors (MAOIs) antidepressants, antibiotics such as linezolid, or intravenous methylene blue. * Previous hypersensitivity reaction to vortioxetine or any components of the formulation. Angioedema has been reported in patients treated with vortioxetine. * Serotonin syndrome. * Abnormal bleeding. * Previous history of mania/hypomania. * Angle closure glaucoma. * Hyponatremia. * Moderate hepatic impairment. * Active seizure disorder/epilepsy, not controlled by medication * Presence of any unstable medical conditions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Least Square Mean Change in Baseline to Week 8 on Z-score in Combined Digit Symbol Substitution Test (DSST) | Weeks 0-8 | This measures the least square mean change in baseline-to-end point on z-score on the combined DSST. Depicted is the least square (LS) mean \[standard error of mean (SEM)\] change in DSST z-scores from baseline to week 8 using an independent covariance matrix with time as a categorical variable, adjusted for the type of cognitive test (Pen/Paper versus Online CogState version). Larger least squares mean indicates a higher predicted or adjusted average outcome for that group or condition compared to others. In other words, if you have a higher least squares mean for a treatment group, it suggests that, after adjusting for the effects of other variables, that group tends to have a higher average outcome, indicating better performance. A least squares mean of 0 indicates that the groups has no difference in average outcome. There is no fixed maximum or minimum for LS Means. They are derived from the data and can, in principle, take any real value (positive, negative, or zero) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline to Endpoint Change in World Health Organization Wellbeing Scale, 5-item (WHO-5) | Weeks 0-8 | This measures the least square mean change in baseline-to-end point on scores on the WHO-5. Depicted is the least square (LS) mean \[standard error of mean (SEM)\] change in WHO-5 from baseline to week 8. Larger least squares mean indicates a higher predicted or adjusted average outcome for that group or condition compared to others. In other words, if you have a higher least squares mean for a treatment group, it suggests that, after adjusting for the effects of other variables, that group tends to have a higher average outcome, indicating better performance. A least squares mean of 0 indicates that the groups has no difference in average outcome. There is no fixed maximum or minimum for LS Means. They are derived from the data and can, in principle, take any real value (positive, negative, or zero) |
| Baseline-to-endpoint (i.e., Week 8) Change in the Quick Inventory of Depressive Symptomology, Self Report (QIDS-SR-16) | Week 0-8 | This measures the least square mean change in baseline-to-end point on the QIDS-SR-16. A negative least squares estimate for the QIDS-SR-16 score from baseline to week 8 indicates a reduction in depressive symptoms. Specifically, it implies that, on average, the QIDS-SR-16 scores have decreased over the 8-week period. Since lower QIDS-SR-16 scores correspond to less severe depressive symptoms, a negative change is a positive outcome, showing improvement. A least squares mean of 0 indicates that the groups has no difference in average outcome. There is no fixed maximum or minimum for LS Means. They are derived from the data and can, in principle, take any real value (positive, negative, or zero) |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vortioxetine Participants aged 18-64 years: start at 10 mg vortioxetine once daily for the first 2 weeks, then dosed up to 20 mg vortioxetine once daily for weeks 2-8.
Participants aged 65+ years: start at 5 mg vortioxetine once daily for the first 2 weeks, then dosed up to 10 mg vortioxetine once daily for weeks 2-8.
Vortioxetine: Participants aged 18-64 years receiving vortioxetine will be provided 10 mg/day on days 1-14 of the treatment period, and will be titrated to 20 mg/day at the start of week 3 (day 15) based on study clinician judgment. For the remaining 6 weeks, the dose of vortioxetine will be 20 mg/day, unless adjudicated otherwise by a study clinician.
Per product monograph, participants aged 65+ years receiving vortioxetine will be provided 5 mg/day on days 1-14 of the treatment period, and will be titrated to 10 mg/day at the start of week 3 (day 15) based on study clinician judgment. For the remaining 6 weeks, the dose of vortioxetine will be 10 mg/day, unless adjudicated otherwise by a study clinician. | 75 |
| Placebo Placebo capsule taken once daily for weeks 0-8.
Placebo: A placebo pill will be taken once daily. | 74 |
| Total | 149 |
Baseline characteristics
| Characteristic | Total | Placebo | Vortioxetine |
|---|---|---|---|
| Age, Continuous | 44.36 years STANDARD_DEVIATION 12.21 | 44.94 years STANDARD_DEVIATION 12.03 | 43.65 years STANDARD_DEVIATION 12.26 |
| Combined Digit Symbol Substitution Test | -0.07127 units on a scale STANDARD_DEVIATION 1.002 | -0.21 units on a scale STANDARD_DEVIATION 0.96 | -0.02 units on a scale STANDARD_DEVIATION 0.91 |
| Computurized Digit Symbol Substitution Test (DSST) | 47.36 Total Number of Symbols STANDARD_DEVIATION 10.5 | 46.35 Total Number of Symbols STANDARD_DEVIATION 10.75 | 48.40 Total Number of Symbols STANDARD_DEVIATION 10.11 |
| Confirmed COVID Diagnosis | 118 participants | 59 participants | 59 participants |
| Highest Education = College/University | 89 participants | 42 participants | 47 participants |
| Highest Education - Graduate School | 28 participants | 18 participants | 10 participants |
| Highest Education = Highschool | 32 participants | 14 participants | 18 participants |
| Lifetime Major Depressive Disorder Diagnosis | 57 participants | 25 participants | 32 participants |
| Race/Ethnicity, Customized Caucasian | 113 participants | 55 participants | 58 participants |
| Race/Ethnicity, Customized Non-Caucasian | 36 participants | 19 participants | 17 participants |
| Region of Enrollment Canada | 149 participants | 74 participants | 75 participants |
| Remote Participation in Trial, n (%) | 78 participants | 40 participants | 38 participants |
| Sex: Female, Male Female | 98 Participants | 47 Participants | 51 Participants |
| Sex: Female, Male Male | 51 Participants | 27 Participants | 24 Participants |
| The 5-item World Health Organization Well-Being Index (WHO-5) | 9.808 Total Score STANDARD_DEVIATION 4.245 | 9.757 Total Score STANDARD_DEVIATION 9.808 | 9.808 Total Score STANDARD_DEVIATION 4.579 |
| The Quick Inventory of Depressive Symptomatology-Self-report (QIDS-SR16) | 10.18 Total Score STANDARD_DEVIATION 4.33 | 10.32 Total Score STANDARD_DEVIATION 4.37 | 10.03 Total Score STANDARD_DEVIATION 4.33 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 74 |
| other Total, other adverse events | 47 / 75 | 34 / 74 |
| serious Total, serious adverse events | 0 / 75 | 0 / 74 |
Outcome results
Primary
Least Square Mean Change in Baseline to Week 8 on Z-score in Combined Digit Symbol Substitution Test (DSST)
This measures the least square mean change in baseline-to-end point on z-score on the combined DSST. Depicted is the least square (LS) mean \[standard error of mean (SEM)\] change in DSST z-scores from baseline to week 8 using an independent covariance matrix with time as a categorical variable, adjusted for the type of cognitive test (Pen/Paper versus Online CogState version). Larger least squares mean indicates a higher predicted or adjusted average outcome for that group or condition compared to others. In other words, if you have a higher least squares mean for a treatment group, it suggests that, after adjusting for the effects of other variables, that group tends to have a higher average outcome, indicating better performance. A least squares mean of 0 indicates that the groups has no difference in average outcome. There is no fixed maximum or minimum for LS Means. They are derived from the data and can, in principle, take any real value (positive, negative, or zero)
Time frame: Weeks 0-8
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine | Least Square Mean Change in Baseline to Week 8 on Z-score in Combined Digit Symbol Substitution Test (DSST) | 0.332 score on a scale | Standard Error 0.0752 |
| Placebo | Least Square Mean Change in Baseline to Week 8 on Z-score in Combined Digit Symbol Substitution Test (DSST) | 0.184 score on a scale | Standard Error 0.0934 |
Secondary
Baseline to Endpoint Change in World Health Organization Wellbeing Scale, 5-item (WHO-5)
This measures the least square mean change in baseline-to-end point on scores on the WHO-5. Depicted is the least square (LS) mean \[standard error of mean (SEM)\] change in WHO-5 from baseline to week 8. Larger least squares mean indicates a higher predicted or adjusted average outcome for that group or condition compared to others. In other words, if you have a higher least squares mean for a treatment group, it suggests that, after adjusting for the effects of other variables, that group tends to have a higher average outcome, indicating better performance. A least squares mean of 0 indicates that the groups has no difference in average outcome. There is no fixed maximum or minimum for LS Means. They are derived from the data and can, in principle, take any real value (positive, negative, or zero)
Time frame: Weeks 0-8
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine | Baseline to Endpoint Change in World Health Organization Wellbeing Scale, 5-item (WHO-5) | 1.759 score on a scale | Standard Error 0.489 |
| Placebo | Baseline to Endpoint Change in World Health Organization Wellbeing Scale, 5-item (WHO-5) | 1.107 score on a scale | Standard Error 0.59 |
Secondary
Baseline-to-endpoint (i.e., Week 8) Change in the Quick Inventory of Depressive Symptomology, Self Report (QIDS-SR-16)
This measures the least square mean change in baseline-to-end point on the QIDS-SR-16. A negative least squares estimate for the QIDS-SR-16 score from baseline to week 8 indicates a reduction in depressive symptoms. Specifically, it implies that, on average, the QIDS-SR-16 scores have decreased over the 8-week period. Since lower QIDS-SR-16 scores correspond to less severe depressive symptoms, a negative change is a positive outcome, showing improvement. A least squares mean of 0 indicates that the groups has no difference in average outcome. There is no fixed maximum or minimum for LS Means. They are derived from the data and can, in principle, take any real value (positive, negative, or zero)
Time frame: Week 0-8
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine | Baseline-to-endpoint (i.e., Week 8) Change in the Quick Inventory of Depressive Symptomology, Self Report (QIDS-SR-16) | -3.351 units on a scale | Standard Error 0.524 |
| Placebo | Baseline-to-endpoint (i.e., Week 8) Change in the Quick Inventory of Depressive Symptomology, Self Report (QIDS-SR-16) | -1.756 units on a scale | Standard Error 0.503 |