Vortioxetine for Post-COVID-19 Condition

Study Overview
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Brief Summary
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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
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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.

Official Title
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Randomized, Double-Blinded, Placebo-Controlled Study Evaluating Vortioxetine for Cognitive Deficits in Persons With Post-COVID-19 Condition

Conditions
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Post-COVID-19 Condition, Post-COVID-19 Syndrome, Cognitive Impairment

Intervention / Treatment
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* Drug: Vortioxetine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vortioxetine<br>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. | Drug: Vortioxetine<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Placebo capsule taken once daily for weeks 0-8. | Drug: Placebo<br>* A placebo pill will be taken once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Digit Symbol Substitution Test (DSST) | Baseline-to-endpoint (i.e., Week 8) change in Digit Symbol Substitution Test (DSST) (Pen/Paper Version and Online CogState Version as part of the CogState Online Cognitive Battery). Remote participants will not complete the pen/paper version of the DSST. | Weeks 0-8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CogState Online Cognitive Battery | Baseline-to-endpoint (i.e., Week 8) change in CogState Online Cognitive Battery scores. The CogState Online Cognitive Battery (https://www.cogstate.com/) employed in the present trial will consist of four tests: Domain: Executive Function, Operation: Digit Symbol substitution test (CogState DSST) Domain: Attention, Operation: Operation: Choice Reaction Time (2 CogState tests: CogState Detection Test, CogState Identification Test) Domain: Memory, Operation: Visual Learning (CogState One Card Learning Test) | Weeks 0-8 | 
| Trails Making Test (TMT)-A/B | Baseline-to-endpoint (i.e., Week 8) change in the Trails Making Test (TMT)-A/B will be used to assess change in cognitive function. | Weeks 0-8 | 
| Rey's auditory verbal learning test (RAVLT) | Baseline-to-endpoint (i.e., Week 8) change in the Rey's auditory verbal learning test (RAVLT) will be used to assess change in verbal memory. | Weeks 0-8 | 
| Perceived Deficits Questionnaire, 20-item (PDQ-20) | Baseline-to-endpoint (i.e., Week 8) change in Perceived Deficits Questionnaire, 20-item (PDQ-20) will be used to assess change in subjective cognitive functioning. | Weeks 0-8 | 
| Fatigue Severity Scale (FSS) | Baseline-to-endpoint (i.e., Week 8) change in the Fatigue Severity Scale (FSS) will be used to assess change in severity and impact of fatigue. | Weeks 0-8 | 
| Snaith Hamilton Pleasure Rating Scale (SHAPS) | Baseline-to-endpoint (i.e., Week 8) change in the Snaith Hamilton Pleasure Rating Scale (SHAPS) will be used to assess change in four domains of pleasure response/hedonic experience: interest/pastimes, social interaction, sensory experience, and food/drink. | Weeks 0-8 | 
| Patient Health Questionnaire, 9-item (PHQ-9) | Baseline-to-endpoint (i.e., Week 8) change in the Patient Health Questionnaire, 9-item (PHQ-9) will be used to assess change across self-rated depressive symptoms. | Weeks 0-8 | 
| Generalized Anxiety Scale, 7-item (GAD-7) | Baseline-to-endpoint (i.e., Week 8) change in the Generalized Anxiety Scale, 7-item (GAD-7) will be used to assess change across self-rated general anxiety symptoms. | Weeks 0-8 | 
| World Health Organization Wellbeing Scale, 5-item (WHO-5) | Baseline-to-endpoint (i.e., Week 8) change in the World Health Organization Wellbeing Scale, 5-item (WHO-5) will be used to assess change in subjective well-being. | Weeks 0-8 | 
| EuroQol, 5-dimension, 5-level (EQ-5D-5L) | Baseline-to-endpoint (i.e., Week 8) change in the EuroQol, 5-dimension, 5-level (EQ-5D-5L) will be used to assess change in quality of daily life across 5 dimensions (mobility, capacity for self-care, conduct of usual activities, pain/discomfort and anxiety/depression). | Weeks 0-8 | 
| Sheehan Disability Scale (SDS) | Baseline-to-endpoint (i.e., Week 8) change in the Sheehan Disability Scale (SDS) will be used to assess change in functional impairment due to disability. | Weeks 0-8 | 
| Post-Covid Functional Scale (PCFS) | Baseline-to-endpoint (i.e., Week 8) change in the Post-Covid Functional Scale (PCFS) will be used to assess change in functional status over time following COVID-19 infection. | Weeks 0-8 | 
| Behaviour Inhibition System/Behavioural Activation System (BIS/BAS) | Baseline-to-endpoint (i.e., Week 8) change in the BIS/BAS will be used to assess change in the behavioral inhibition system and the behavioural activation system over time following COVID-19 infection. | Weeks 0-8 | 
| International Physical Activity Questionnaire (IPAQ) | Baseline-to-endpoint (i.e., Week 8) change in the International Physical Activity Questionnaire (IPAQ) will be used to assess changes in various intensities of physical activity as well as sitting time weekly over time following COVID-19 infection. | Weeks 0-8 | 
| Effort-Expenditure for Rewards Task (EEfRT) | Baseline-to-endpoint (i.e., Week 8) change in the Effort-Expenditure for Rewards Task (EEfRT) will be used to assess changes in motivation and reward over time following COVID-19 infection. | Week 0-8 | 
| Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR-16) | Baseline-to-endpoint (i.e., Week 8) change in the Quick Inventory of Depressive Symptomology, Self Report (QIDS-SR-16) will be used to assess changes in severity of subjective depressive symptoms over time following COVID-19 infection. | Week 0-8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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