Vortioxetine for Post-COVID-19 Condition

NCT05047952 | Completed Phase 2 Results

• 1 other identifier: BCDF002
• Study Type: interventional
• Target: 149
• Locations: 1 country
• Sites: 1

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.

Conditions

Post-COVID-19 Condition; Post-COVID-19 Syndrome; Cognitive Impairment

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

Outcome Measures

Primary Outcomes (1)

• 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)

  Weeks 0-8

Secondary Outcomes (2)

• Baseline to Endpoint Change in World Health Organization Wellbeing Scale, 5-item (WHO-5)

  Weeks 0-8

• Baseline-to-endpoint (i.e., Week 8) Change in the Quick Inventory of Depressive Symptomology, Self Report (QIDS-SR-16)

  Week 0-8

Study Arms (2)

Vortioxetine

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

Placebo capsule taken once daily for weeks 0-8.

Drug: Placebo

Interventions

Vortioxetine DRUG

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.

Vortioxetine

Placebo DRUG

A placebo pill will be taken once daily.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Brain and Cognition Discovery Foundation: lead

Study Sites (1)

Brain and Cognition Discovery Foundation (BCDF)

Toronto, Ontario, M5S 1M2, Canada

Location

Related Publications (26)

• 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.

  PMID: 32665317 BACKGROUND

• 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.

  PMID: 34153235 BACKGROUND

• 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.

  PMID: 32644129 BACKGROUND

• 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.

  PMID: 33692530 BACKGROUND

• 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.

  PMID: 33055076 BACKGROUND

• 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.

  PMID: 32730619 BACKGROUND

• 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.

  PMID: 33180097 BACKGROUND

• 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.

  PMID: 33536545 BACKGROUND

• 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.

  PMID: 29689693 BACKGROUND

• 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.

  PMID: 27780334 BACKGROUND

• 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.

  PMID: 27312740 BACKGROUND

• 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.

  PMID: 30766492 BACKGROUND

• 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.

  PMID: 31404802 BACKGROUND

• 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.

  PMID: 33516560 BACKGROUND

• 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.

  PMID: 31530216 BACKGROUND

• 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.

  PMID: 29057467 BACKGROUND

• 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.

  PMID: 32174477 BACKGROUND

• 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.

  PMID: 25687662 BACKGROUND

• 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.

  PMID: 34973396 BACKGROUND

• 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.

  PMID: 34951953 BACKGROUND

• 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.

  PMID: 34308300 BACKGROUND

• Liao S, Teopiz KM, Kwan ATH, Le GH, Wong S, Ballum H, Rhee TG, Badulescu S, Cao B, Guo Z, Meshkat S, Phan L, Subramaniapillai M, Ho R, McIntyre RS. Relationship between anhedonia and psychosocial functioning in post-COVID-19 condition: a post-hoc analysis. Curr Med Res Opin. 2024 Aug;40(8):1407-1411. doi: 10.1080/03007995.2024.2374510. Epub 2024 Jul 8.

  PMID: 38954402 DERIVED

• Teopiz KM, Kwan ATH, Le GH, Guo Z, Badulescu S, Ceban F, Meshkat S, Di Vincenzo JD, d'Andrea G, Cao B, Ho R, Rhee TG, Dev DA, Phan L, Subramaniapillai M, Mansur RB, Rosenblat JD, McIntyre RS. Association between fatigue and depressive symptoms in persons with post-COVID-19 condition: a post hoc analysis. Curr Med Res Opin. 2024 Jul;40(7):1203-1209. doi: 10.1080/03007995.2024.2360647. Epub 2024 Jun 11.

  PMID: 38860901 DERIVED

• Kwan ATH, Guo Z, Ceban F, Le GH, Wong S, Teopiz KM, Rhee TG, Ho R, Di Vincenzo JD, Badulescu S, Meshkat S, Cao B, Rosenblat JD, d'Andrea G, Dev DA, Phan L, Subramaniapillai M, McIntyre RS. Assessing the Effects of Metabolic Disruption, Body Mass Index and Inflammation on Depressive Symptoms in Post-COVID-19 Condition: A Randomized Controlled Trial on Vortioxetine. Adv Ther. 2024 May;41(5):1983-1994. doi: 10.1007/s12325-024-02826-9. Epub 2024 Mar 23.

  PMID: 38520501 DERIVED

• Kwan ATH, Le GH, Guo Z, Ceban F, Teopiz KM, Rhee TG, Ho R, Di Vincenzo JD, Badulescu S, Meshkat S, Cao B, Rosenblat JD, Dev DA, Phan L, Subramaniapillai M, McIntyre RS. Impacts of metabolic disruption, body mass index and inflammation on cognitive function in post-COVID-19 condition: a randomized controlled trial on vortioxetine. Ann Gen Psychiatry. 2024 Feb 29;23(1):10. doi: 10.1186/s12991-024-00494-1.

  PMID: 38424537 DERIVED

• Le GH, Kwan ATH, Wong S, Guo Z, Teopiz KM, Badulescu S, Meshkat S, d'Andrea G, Ho R, Rhee TG, Cao B, Phan L, Rosenblat JD, Mansur RB, Subramaniapillai M, McIntyre RS. Impact of Elevated Body Mass Index (BMI) on Hedonic Tone in Persons with Post-COVID-19 Condition: A Secondary Analysis. Adv Ther. 2024 Feb;41(2):686-695. doi: 10.1007/s12325-023-02760-2. Epub 2023 Dec 19.

  PMID: 38114867 DERIVED

Related Links

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

MeSH Terms

Conditions

Post-Acute COVID-19 Syndrome; Cognitive Dysfunction; Fatigue; Mental Fatigue; Cognition Disorders

Interventions

Vortioxetine

Condition Hierarchy (Ancestors)

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Post-Infectious Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neurocognitive Disorders; Mental Disorders; Signs and Symptoms; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

participants not stratified as part of eligibility on the basis of having a predetermined threshold of objective cognitive impairment prior to enrolment. Participants in our study were primarily recruited via media announcements including presentations at Post COVID-19 Condition online groups. Our sample was not recruited from a medical clinic including "Post COVID-19 Condition clinics." Majority of participants were Caucasian; it is recognized that our results may not generalizable.

Results Point of Contact

• Title: Dr. Roger S. McIntyre
• Organization: Brain and Cognition Discovery Foundation

roger.mcintyre@bcdf.org

416-669-5279

Study Officials

• Roger S. McIntyre, MD, FRCPC

  Brain and Cognition Discovery Foundation

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 12, 2021
• First Posted: September 17, 2021
• Study Start: September 16, 2021
• Primary Completion: February 22, 2023
• Study Completion: February 22, 2023
• Last Updated: January 16, 2025
• Results First Posted: January 16, 2025

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)