Vortioxetine for Post-COVID-19 Condition

Cognitive Impairment Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05047952
• Other study ID #: BCDF002
• Status: Completed
• Phase: Phase 2
• Start date: September 16, 2021
• Est. completion date: February 22, 2023

Study information

• Verified date: May 2023
• Source: Brain and Cognition Discovery Foundation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 200
• Est. completion date: February 22, 2023
• Est. primary completion date: February 22, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cognitive Impairment
• COVID-19
• Disease
• Post-COVID-19 Syndrome
• Syndrome

Intervention

Drug:
• 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.
• Placebo
A placebo pill will be taken once daily.

Locations

Country	Name	City	State
Canada	Brain and Cognition Discovery Foundation (BCDF)	Toronto	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
Brain and Cognition Discovery Foundation

Country where clinical trial is conducted

Canada, 

References & Publications (21)

Burke MJ, Del Rio C. Long COVID has exposed medicine's blind-spot. Lancet Infect Dis. 2021 Aug;21(8):1062-1064. doi: 10.1016/S1473-3099(21)00333-9. Epub 2021 Jun 18. No abstract available. — View Citation

Cao B, Park C, Rosenblat JD, Chen Y, Iacobucci M, Subramaniapillai M, Mansur RB, Zuckerman H, Lee Y, McIntyre RS. Changes in sleep predict changes in depressive symptoms in depressed subjects receiving vortioxetine: An open-label clinical trial. J Psychopharmacol. 2019 Nov;33(11):1388-1394. doi: 10.1177/0269881119874485. Epub 2019 Sep 18. — View Citation

Cao B, Park C, Subramaniapillai M, Lee Y, Iacobucci M, Mansur RB, Zuckerman H, Phan L, McIntyre RS. The Efficacy of Vortioxetine on Anhedonia in Patients With Major Depressive Disorder. Front Psychiatry. 2019 Jan 31;10:17. doi: 10.3389/fpsyt.2019.00017. eCollection 2019. — View Citation

Carfi A, Bernabei R, Landi F; Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19. JAMA. 2020 Aug 11;324(6):603-605. doi: 10.1001/jama.2020.12603. — View Citation

Ceban F, Ling S, Lui LMW, Lee Y, Gill H, Teopiz KM, Rodrigues NB, Subramaniapillai M, Di Vincenzo JD, Cao B, Lin K, Mansur RB, Ho RC, Rosenblat JD, Miskowiak KW, Vinberg M, Maletic V, McIntyre RS. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain Behav Immun. 2022 Mar;101:93-135. doi: 10.1016/j.bbi.2021.12.020. Epub 2021 Dec 29. — View Citation

Christensen MC, Loft H, McIntyre RS. Vortioxetine improves symptomatic and functional outcomes in major depressive disorder: A novel dual outcome measure in depressive disorders. J Affect Disord. 2018 Feb;227:787-794. doi: 10.1016/j.jad.2017.11.081. Epub 2017 Nov 16. — View Citation

Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re'em Y, Redfield S, Austin JP, Akrami A. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021 Aug;38:101019. doi: 10.1016/j.eclinm.2021.101019. Epub 2021 Jul 15. — View Citation

Fagiolini A, Florea I, Loft H, Christensen MC. Effectiveness of Vortioxetine on Emotional Blunting in Patients with Major Depressive Disorder with inadequate response to SSRI/SNRI treatment. J Affect Disord. 2021 Mar 15;283:472-479. doi: 10.1016/j.jad.2020.11.106. Epub 2020 Nov 19. — View Citation

Hoertel N, Sanchez-Rico M, Vernet R, Beeker N, Jannot AS, Neuraz A, Salamanca E, Paris N, Daniel C, Gramfort A, Lemaitre G, Bernaux M, Bellamine A, Lemogne C, Airagnes G, Burgun A, Limosin F; AP-HP / Universities / INSERM COVID-19 Research Collaboration and AP-HP COVID CDR Initiative. Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study. Mol Psychiatry. 2021 Sep;26(9):5199-5212. doi: 10.1038/s41380-021-01021-4. Epub 2021 Feb 4. — View Citation

Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, Miller JP, Yang L, Yingling M, Avidan MS, Reiersen AM. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA. 2020 Dec 8;324(22):2292-2300. doi: 10.1001/jama.2020.22760. — View Citation

Mahableshwarkar AR, Zajecka J, Jacobson W, Chen Y, Keefe RS. A Randomized, Placebo-Controlled, Active-Reference, Double-Blind, Flexible-Dose Study of the Efficacy of Vortioxetine on Cognitive Function in Major Depressive Disorder. Neuropsychopharmacology. 2015 Jul;40(8):2025-37. doi: 10.1038/npp.2015.52. Epub 2015 Feb 17. Erratum In: Neuropsychopharmacology. 2016 Nov;41(12 ):2961. — View Citation

Mahase E. Covid-19: What do we know about "long covid"? BMJ. 2020 Jul 14;370:m2815. doi: 10.1136/bmj.m2815. No abstract available. — View Citation

Mahase E. Long covid could be four different syndromes, review suggests. BMJ. 2020 Oct 14;371:m3981. doi: 10.1136/bmj.m3981. No abstract available. — View Citation

McIntyre RS, Florea I, Tonnoir B, Loft H, Lam RW, Christensen MC. Efficacy of Vortioxetine on Cognitive Functioning in Working Patients With Major Depressive Disorder. J Clin Psychiatry. 2017 Jan;78(1):115-121. doi: 10.4088/JCP.16m10744. — View Citation

McIntyre RS, Harrison J, Loft H, Jacobson W, Olsen CK. The Effects of Vortioxetine on Cognitive Function in Patients with Major Depressive Disorder: A Meta-Analysis of Three Randomized Controlled Trials. Int J Neuropsychopharmacol. 2016 Jun 15;19(10):pyw055. doi: 10.1093/ijnp/pyw055. — View Citation

Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffmann J, Shchendrygina A, Escher F, Vasa-Nicotera M, Zeiher AM, Vehreschild M, Nagel E. Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020 Nov 1;5(11):1265-1273. doi: 10.1001/jamacardio.2020.3557. Erratum In: JAMA Cardiol. 2020 Nov 1;5(11):1308. — View Citation

Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV; WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022 Apr;22(4):e102-e107. doi: 10.1016/S1473-3099(21)00703-9. Epub 2021 Dec 21. — View Citation

Subramaniapillai M, Mansur RB, Zuckerman H, Park C, Lee Y, Iacobucci M, Cao B, Ho R, Lin K, Phan L, McIntyre RS. Association between cognitive function and performance on effort based decision making in patients with major depressive disorder treated with Vortioxetine. Compr Psychiatry. 2019 Oct;94:152113. doi: 10.1016/j.comppsych.2019.07.006. Epub 2019 Jul 24. — View Citation

Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, Pujol JC, Klaser K, Antonelli M, Canas LS, Molteni E, Modat M, Jorge Cardoso M, May A, Ganesh S, Davies R, Nguyen LH, Drew DA, Astley CM, Joshi AD, Merino J, Tsereteli N, Fall T, Gomez MF, Duncan EL, Menni C, Williams FMK, Franks PW, Chan AT, Wolf J, Ourselin S, Spector T, Steves CJ. Attributes and predictors of long COVID. Nat Med. 2021 Apr;27(4):626-631. doi: 10.1038/s41591-021-01292-y. Epub 2021 Mar 10. Erratum In: Nat Med. 2021 Jun;27(6):1116. — View Citation

Talmon M, Rossi S, Pastore A, Cattaneo CI, Brunelleschi S, Fresu LG. Vortioxetine exerts anti-inflammatory and immunomodulatory effects on human monocytes/macrophages. Br J Pharmacol. 2018 Jan;175(1):113-124. doi: 10.1111/bph.14074. Epub 2017 Nov 28. — View Citation

Tomaz VS, Chaves Filho AJM, Cordeiro RC, Juca PM, Soares MVR, Barroso PN, Cristino LMF, Jiang W, Teixeira AL, de Lucena DF, Macedo DS. Antidepressants of different classes cause distinct behavioral and brain pro- and anti-inflammatory changes in mice submitted to an inflammatory model of depression. J Affect Disord. 2020 May 1;268:188-200. doi: 10.1016/j.jad.2020.03.022. Epub 2020 Mar 6. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   An Analysis of the Prolonged COVID-19 Symptoms Survey by Patient-Led Research Team
•   Rehabilitation in the wake of Covid-19 - A phoenix from the ashes; British Society of Rehabilitation Medicine (BSRM)
•   Study With Vortioxetine on Emotional Functioning in Patients With Depression (COMPLETE)
•   World Health Organization (WHO) COVID-19 Dashboard