Clinical trial NCT05047952
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
Sponsor: Brain and Cognition Discovery Foundation
Start date: 2021-09-16; Completion date: 2023-02-22
Enrollment: 149 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: Placebo capsule taken once daily for weeks 0-8.
Interventions: intervention 1: Vortioxetine intervention 2: Placebo
Intervention descriptions: intervention 1: 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. intervention 2: A placebo pill will be taken once daily.

Protocol documents:
Prot_SAP_000.pdf: 
 
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Randomized, Double-Blinded, Placebo-Controlled Study 
Evaluating Vortioxetine for Cognitive Deficits in Persons 
with Post-COVID-19 Condition (Protocol Number: 
BCDF002) 
 
 
 
Principal Investigator:  
Dr. Roger S. McIntyre, M.D., FRCPC 
Chairman and Executive Director, 
Brain and Cognition Discovery Foundation (BCDF) 
77 Bloor Street West, Suite 600, Toronto, ON, M5S 1M2 
longcovid@bcdfoundation.ca 
 
Sub-Investigator (Study Physician): 
Dr. Pawel Drzadzewski, M.D.  
Family Physician, CRTCE/KJK HealthPlex 
1100 Dundas Street West, Unit #4, Mississauga, ON, L5C 4E7 
 
Additional Investigators: 
Dr. Simon J. Graham, Ph.D., P.Eng 
Department of Medical Biophysics, Sunnybrook Research Institute 
 
Dr. Bradley MacIntosh, Ph.D. 
Department of Medical Biophysics, Sunnybrook Research Institute 
 
Dr. Matthew J. Burke, M.D., FRCPC 
Cognitive Neurologist, Neuropsychiatry Program 
Associate Scientist, Hurvitz Brain Sciences Research Program 
Sunnybrook Health Sciences Centre 
 
 
 


 
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2 
 
 
Tables of Contents 
 
Background 
3 
Hypotheses 
3 
Study Design 
4 
Study Population 
4 
Recruitment 
6 
Study Visits 
6 
Sample Size 
10 
Feasibility 
10 
Study Flow 
20 
Conditions for Withdrawal From the Study 
18 
Participant Compensation 
19 
Study Medication: Vortioxetine 
19 
Data Handling 
22 
Data Collection and Retention 
22 
Participant Protection 
22 
Statistical analysis plan 
27 
Publication Plan 
28 
Documentation 
28 
Contract Details 
28 
References 
29 
 
 
 
Background 
Since the World Health Organization (WHO) declaration of COVID-19 as a global pandemic in 
March 2020, it is estimated that over 375 million people have tested positive for the virus globally 


 
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3 
 
1. Consensus exists that the true infection rate is considerably higher, with estimates of 
approximately 5-10 fold greater, suggesting 1.9 to 3.75 billion persons have been infected with 
COVID-19. 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) 1,23. 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 4,5. 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’ 6. 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  2,6.  
 
Consensus exists that the phenomenology of post-COVID-19 condition is subserved by 
disturbance in immune-inflammatory systems 7. Currently, no treatment is identified as safe and 
effective for post-COVID-19 condition 7,8. 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 7–9. 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 10–12. The candidate treatment would be preferred to target biological systems 
subserving circadian rhythms, as well as reward and reinforcement brain mechanisms. The profile 
of the candidate treatment should also have preliminary evidence documenting favourable 
modulatory effects on circulating pro-inflammatory cytokines, as well as immune cellular systems 
(e.g., macrophages). Preliminary evidence suggests that some antidepressants (e.g., SSRIs) are 
capable of reducing respiratory complications secondary to COVID-19 13,14. Putative mechanisms 
implicated include sigma-1 agonism and acid sphingomyelinase 13. A limitation of SSRIs, 
however, for specifically targeting post-COVID-19 condition, is that they are not proven to be pro-
cognitive and/or beneficial for reward systems and are, instead, reported to have, in some cases, 
dyscognitive and reward blunting effects (e.g., emotional blunting) 13,15–17. 
 
Vortioxetine is established as pro-cognitive, as evidenced by significant improvement on both 
subjective and objective measures 1819,20. Vortioxetine is also documented to improve anticipatory 
and consummatory measures of reward function/anhedonia as evaluated by validated reward 
paradigms, as well as the Snaith Hamilton Pleasure Scale (SHAPS) 21,22. Vortioxetine also 
improves general functioning 
18. Furthermore, vortioxetine has demonstrated significant 
improvement on measures of motivation and energy 23,24. Moreover, vortioxetine is not associated 
with emotional blunting and has preliminary evidence of improving sleep behaviour and circadian 
rhythms 23,25. 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 26,27. 
Hypotheses 
Herein, we hypothesize that vortioxetine (5-20 mg) will be more effective than placebo in the 
treatment of cognitive impairment in persons with post-COVID-19 condition.  


 
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Study Design 
Eight-week, randomized, double-blinded, placebo-controlled clinical trial  
● Eight-week intervention (i.e., weeks 0-8) 
● Two-week drug discontinuation and safety follow-up period (i.e., weeks 8-10) 
 
Primary Endpoint: Week 8 
Outcomes 
Primary Outcomes 
● 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.  
 
Secondary Outcomes 
● Baseline-to-endpoint change in: 
o CogState Online Cognitive Battery 
o Trails Making Test (TMT)-A/B 
o Rey's auditory verbal learning test (RAVLT) 
o Perceived Deficits Questionnaire, 20-item (PDQ-20) 
o Fatigue Severity Scale (FSS) 
○ Snaith Hamilton Pleasure Rating Scale (SHAPS) 
○ Generalized Anxiety Scale, 7-item (GAD-7) 
○ World Health Organization Wellbeing Scale, 5-item (WHO-5) 
○ EuroQol, 5-dimension, 5-level (EQ-5D-5L) 
○ Sheehan Disability Scale (SDS) 
○ Post-Covid Functional Scale (PCFS) 
○ fMRI and the Effort Expenditure for Rewards Task (EEfRT) 
○  
○ Behavioural Activation Scale (BAS) 
○ International Physical Activity Questionnaire (IPAQ) 
○ Quick Inventory of Depressive Symptomatology (16-Item) (Self-Report) (QIDS-
SR16) 
● Safety outcomes  
○ Spontaneously reported adverse events 
○ Laboratory (including but not limited to CBC, TSH, electrolytes) 
Study Population  
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 


 
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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.’ 6 
○ 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 their confirmed and 
documented positive polymerase chain reaction (PCR) SARS-CoV-2 test, rapid 
antigen, or antibody test. In lieu of a prior positive test, a signed confirmation of a 
presumptive prior COVID-19 case from a healthcare provider, including the study 
physician, is acceptable.  
● Documented history of SARS-CoV-2 infection with typical symptoms, and requiring 
positive SARS-CoV-2 test (PCR,antigen, or serology) at some point during the course of 
the acute course of illness. In lieu of a prior positive test, a confirmation of a presumptive 
prior COVID-19 case from a healthcare provider, including the study physician, is 
acceptable.  
● 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., ADHD, 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 28–30. 
● 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).  


 
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● 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 (per study physician 
assessment). 
● Presence of any unstable medical conditions. 
Recruitment 
Recruitment will take place via media announcements (e.g., print, social media, public 
broadcasting stations). Announcement of study recruitment will also be provided to primary 
health care providers in Canada. 
Study Visits  
Study visits may be conducted remotely (e.g. zoom), by telephone or in-person. Visits with the 
study physician will primarily occur via a secure online platform (e.g. OTN) or by telephone. If 
required/requested, in-person visits with the study physician may be scheduled.  
Participants may be emailed a secure, unique and anonymized RedCap link to complete self-
report questions at home within 24 hours of their scheduled visit (before or after visit). This is to 
reduce participant burden during the visit with research staff/study physicians. Participants will 


 
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be asked to complete self-report questionnaires at the same time block of the day during all 
study visits (i.e. all mornings, afternoons or evenings). 
Pre-Screen 
Participants will be pre-screened via telephone, email, or an online form to determine if they 
meet above noted inclusion and exclusion criteria.  
 
Screening Visit (Visit 0) 
Once participants provide written, informed consent, they will undergo a comprehensive 
assessment to determine eligibility during the screening visit. Details of assessments completed 
are included in Table 1.  
 
Baseline (Visit 1) 
Participants will undergo the various assessments listed in Table 1. In addition, participants will 
have their blood drawn and may be invited to participate in an optional fMRI scan (see details 
below). Participants will also be assessed by a study physician at one time point between the 
screening and baseline visits and be provided a prescription for vortioxetine. Research staff 
(i.e.research coordinators/research assistants) will dispense the medication to the participant 
based on the direction from the study physician/prescription from the study physician for the first 
two weeks of the study. For remote participants, research staff will mail medication for the first 
two weeks of the study with appropriate temperature monitoring.  
 
Laboratory Assessment: Participants will be asked to fast for 8 hours prior to their baseline (visit 
1) and week 8 (visit 4). Participants will have blood drawn for standard clinical parameters. 
These include glucose, insulin, electrolytes, liver and kidney function tests, lipids, CBC, 
inflammatory markers (e.g. CRP, ESR), albumin and protein. Participants may also have their 
blood drawn for various exploratory secondary analyses (e.g. cytokines). Approximately 20 mL 
of blood will be drawn in 4-5 blood tubes. Two of these tubes will include lavender tubes with 
EDTA for exploratory analyses. A urine or blood pregnancy test will be conducted for all female 
participants.  
 
Remote participants will be provided a blood requisition form via email or mail to have clinical 
blood drawn and analyzed at the participant’s local blood lab facility. Blood will not be collected 
for exploratory purposes from remote participants. Female participants may provide a blood or 
urine sample to the local blood lab to confirm non-pregnancy. Participants may also be mailed a 
home pregnancy test.  
 
Exploratory Blood Analyses: For participants seen in-person, they will be able to volunteer to 
provide a blood sample for exploratory analyses. The sample will be collected at a local blood 
lab (e.g. Mount Sinai Hospital), followed by processing and storage of the sample at the 
Biospecimen Repository and Processing Lab (Lunenfeld-Tanenbaum Research Institute, Sinai 
Health). Participants may also have blood drawn at the same time for clinical purposes at Mount 
Sinai Hospital. The clinical blood tubes will be delivered to another local lab (e.g.Dynacare, 
LifeLabs) for analyses. Alternatively, participants may also have blood drawn separately for 
clinical analyses at a local blood lab near them - this will result in two separate blood draws.   
 


 
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fMRI: A subset of participants may be offered the opportunity to have an fMRI scan completed 
at baseline and endpoint for secondary, exploratory purposes. This is optional and not the 
primary focus of the study. Participants may still participate in the study and decide not to 
participate in this component. During the imaging, participants will be asked to complete a 
cognitive task (e.g. Effort Expenditure for Rewards Task, Trails Making Test A/B). Participants 
will be awarded the amount of money they earn during this task, on top of the standard 
compensation to all participants. Please see “Participant Compensation” for more details.  
 
Week 2 (Visit 2): Participants will complete items listed in Table 1, Week 2 (Visit 2). The study 
physician will determine if the participant is eligible for a dose increase. Research staff 
(i.e.research coordinators/research assistants) will dispense medication to the participant based 
on the direction from the study physician/prescription from the study physician for the next six 
weeks of the study. For remote participants, medication for the remaining six weeks of the study 
will be mailed out as well as medication for discontinuation by research staff with appropriate 
temperature monitoring. 
Week 4 (Visit 3): Participants will complete items listed in Table 1, Week 4 (Visit 3).  
 
Week 8 (Visit 4): Participants will complete items listed in Week 8 (Visit 4). The study physician 
will also discuss transition of care (see below) and/or medication continuation. Participants will 
also have their blood drawn and may be asked to participate in the optional fMRI scan.  
 
Optional Post-Study (Week 10): Clinical visit with physician if the participant is discontinuing the 
study medication and/or as needed. If a participant chooses to continue with the study 
medication, he/she will be asked to follow up with his/her most responsible physician (MRP) for 
ongoing care and this post-study visit would not be needed. Participants will be informed prior to 
signing the consent form that research staff/research physician will not be able to tell them if 
they received drug or placebo when they finish the study at week 8 and they will have to wait 
until the entire study is complete to find out.  
 
Table 1. Study schedule with assessments 
Study Visit 
Screening 
(Visit 0) 
Baseline 
(Visit 1) 
Visit 2 
Visit 3 
End-of-study 
(Visit 4) 
Week 
(-1 to -21 
days from 
baseline) 
0 
 
2 
(+/- 2 days) 
4 
(+/- 2 days) 
8 
(+/- 2 days) 
Consent 
X 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Past COVID-19 Infection 
Information 
X 
 
 
 
 


 
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M.I.N.I 7.0.2 
X 
 
 
 
 
Psychiatric/Medical History 
X 
 
 
 
 
Lifestyle Factors 
X 
 
 
 
 
Current Medications 
X 
X 
X 
X 
X 
Medication Changes  
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
Anthropometrics 
 
X 
X 
 
X 
MoCA 
 
X 
 
 
 
SETS 
 
X 
 
 
 
DSST  
 
X 
X 
 
X 
TMT-A/B 
 
X 
X 
 
X 
RAVLT 
 
X 
X 
 
X 
CogState Online Cognitive 
Battery** 
 
X 
X 
 
X 
PDQ-20 
 
X 
X 
X 
X 
GAD-7 
 
X 
X 
X 
X 
SHAPS 
 
X 
X 
X 
X 
FSS 
 
X 
X 
X 
X 
WHO-5 
 
X 
X 
X 
X 
SDS 
 
X 
X 
X 
X 
BAS 
 
X 
X 
X 
X 
EQ-5D-5L 
 
X 
X 
X 
X 
QIDS-SR16 
 
X 
X 
X 
X 
IPAQ 
 
X 
 
X 
X 
PCFS 
X 
X 
X 
X 
X 
EEfRT 
 
X 
 
 
X 


 
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Physician Assessment* 
X 
 
X 
X 
X 
Laboratory assessments 
 
X 
 
 
X 
fMRI + Cognitive Test 
 
X 
 
 
X 
 
Abbreviations: a:  BAS: Behavioural Activation Scale; DSST: Digit Symbol Substitution Test; 
EQ-5D-5L: 5-Level EQ-5D version; fMRI: functional magnetic resonance imaging; FSS: Fatigue 
Severity Scale; GAD-7: Generalized Anxiety Disorder, 7-item; IPAQ: International Physical 
Activity Questionnaire; EEfRT: Effort Expenditure for Rewards Task ; M.I.N.I: Mini-International 
Neuropsychiatric Interview; MoCA: Montreal Cognitive Assessment; PCFS: Post-Covid 
Functional Scale; PDQ-20: Perceived Deficits Questionnaire, 20-item; Quick Inventory of 
Depressive Symptomatology (16-Item) (Self-Report) (QIDS-SR16); RAVLT: Rey's auditory 
verbal learning test; RPE: Borg Rating of Perceived Exertion Scale; SDS: Sheehan Disability 
Scale; SETS: Stanford Expectations of Treatment Scale; SHAPS: Snaith-Hamilton Pleasure 
Scale; TMT-A/B: Trails Making Test-A/B; WHO-5: World Health Organization Well-Being Index, 
5-item. 
*One physician assessment will be conducted between the baseline and screening visit.  
**May be conducted remotely.  
Sample Size 
● Total recruitment N=200 (i.e., 100 subjects allocated to vortioxetine [5-20 mg] and 
placebo each).  
● The target sample size is based on effect sizes reported by previous clinical trials that 
evaluated the efficacy of antidepressants vs placebo and nutraceuticals in individuals 
with chronic fatigue syndrome 6,23–25. 
● The effect size of vortioxetine on DSST-measured cognitive function is estimated at 
approximately 0.2-0.5 2627. Previous experience without patients enrolled in clinical trials 
(investigator-initiated trials) with vortioxetine as part of the THINC-it tool validation 
indicated that vortioxetine improves measures of processing speed (the prominent 
domain validated by the DSST) of significance with a sample size of 200.  
● It is then estimated that a sample size of 100 per treatment arm would detect clinically 
relevant change with vortioxetine treatment on DSST as the dependent measure 27,31. 
Feasibility 
● It is estimated, based on prior general population research conducted by the BCDF, that 
recruitment will take approximately 12 months. 
● Community research ethics board approval, 2-4 weeks (BCDF is an independent 
research center not requiring university- or hospital-based REB reviews). 
 
Description of Study Procedures 
 
Efficacy Assessments 


 
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Digit Symbol Substitution Test (DSST) 
The DSST is a neuropsychological test sensitive to brain damage, dementia, age and 
depression.32,33. The DSST consists of digit-symbol pairs followed by a list of digits. The 
participant will select the corresponding symbol as fast as possible. The number of correct 
symbols within 90 seconds will be recorded. The test is administered by trained personnel. The 
DSST will be administered at baseline (visit 1), and weeks 2 and 8 visits.  
 
Rey Auditory Verbal Learning Test (RAVLT) 
The RAVLT is a neuropsychological assessment designed to evaluate verbal memory in 
patients aged 16 years and older 34. It is presented as a list-learning paradigm wherein the 
participant is read a list of 15 nouns and is asked to recall as many words from the list as 
possible. After five repetitions of free-recall, a second “interference” list (List B) is presented in 
the same manner, and the participant is asked to recall as many words from List B as possible. 
After the interference trial, the participant is immediately asked to recall the words from List A, 
which they have heard five times previously. After a 20 min delay, the participant is asked to 
again recall the words from List A.  This assessment directly tests recognition memory, as 
opposed to free-recall. The test is administered by trained personnel. The RAVLT will be 
administered at baseline (visit 1), and weeks 2 and 8 visits.  
 
Trail Making Tests A/B (TMT-A/B) 
The TMT-A/B are well established tests sensitive to impairment in multiple cognitive domains, 
including attention, visual memory and processing speed, executive functioning, and overall 
cognitive functioning. The tests are administered by a trained personnel. Participants are asked 
to connect circles in numerical sequence as part of TMT-A and in alternating numerical and 
alphabetical sequence as part of TMT-B (e.g., 1-A-2-B). If a participant makes a mistake, the 
administrator points out the error, and the participant must return to the last correct circle and 
continue the task. The tests are timed and participants are given five minutes to complete each 
test; a shorter time denotes higher performance 35. The TMT- A/B will be administered at 
baseline (visit 1), and weeks 2 and 8 visits.  
 
CogState Online Cognitive Battery 
The CogState Online Cognitive Battery (https://www.cogstate.com/) employed in the present 
trial will consist of four tests: 
Domain: Executive Function  
1. Operation: Digit Symbol substitution test  
Cognitive Test: CogState DSST – Symbols - “In this test, subjects are 
presented with a legend that defines nine symbols, with each symbol 
corresponding to a digit from 1 to 9. The subject is then presented with a 
conveyor belt in the middle of the screen that displays a series of empty 
boxes labelled with a number. The subject must select the symbol that 
corresponds to the number of a given highlighted box from symbol 
options presented at the bottom of the screen. The subject must try to 
place as many correct symbols in the boxes as possible over the duration 
of the test.” 36 


 
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Time: 3 min  
Domain: Attention 
2. Operation: Choice Reaction Time  
Cognitive Test: CogState Detection Test - “The Detection test measures 
processing speed using a simple reaction time paradigm. The on-screen 
instructions ask: “Has the card turned over?”. A playing card is presented 
face down in the center of the screen. The card flips over so it is face up. 
As soon as the card flips over the participant must press “Yes”. The 
participant is encouraged to work as quickly as they can and be as 
accurate as possible.” 36 
 
 
 
Time: 3 min 
3. Operation: Choice Reaction Time 
Cognitive Test: CogState Identification Test - “The Identification test 
measures attention using a choice reaction time paradigm. The on-screen 
instructions ask: “Is the card red?”. A playing card is presented face down 
in the center of the screen. The card flips over so it is face up. As soon as 
it flips over the participant must decide whether the card is red or not. If it 
is red the participant should press “Yes”, and if it is not red the participant 
should press “No”. The participant is encouraged to work as quickly as 
they can and be as accurate as possible.” 36 
Time: 3 min  
Domain: Memory  
4. Operation: Visual Learning  
Cognitive Test: CogState One Card Learning Test - “The One Card 
Learning test measures visual memory using a pattern separation 
paradigm. The on-screen instructions ask: “Have you seen this card 
before in this test?”. A playing card is presented face up in the center of 
the screen and the participant must decide whether they have seen the 
card before in this test. The participant is encouraged to work as quickly 
as they can and be as accurate as possible.” 36 
Time: 6 min 
 
Each participant will be completing the battery twice on the same day to assess test reliability 
and as an objective measure of fatigue.The CogState Online Cognitive Battery will be 
administered at baseline (visit 1), and weeks 2 and 8 visits.  
 
Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR-16) 
The QIDS-SR-16 37 is a 16-item self-rated scale designed to assess the severity of depressive 
symptoms in the nine diagnostic symptom domains of a major depressive episode, exclusive of 
atypical or melancholic symptoms, over the past 7 days. The QIDS-SR-16 is sensitive to change 
with various treatments, demonstrating its utility in research settings. The total score ranges 
from 0 to 27 with 0 representing no depression and 27 representing severe depression. The 
total score is the sum of the 9 symptom domains. The QIDS-SR-16 will be administered at 
baseline, and weeks 2, 4, and 8 visits.  
 


 
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Patient Health Questionnaire, 9-item (PHQ-9) 
The PHQ-9 is a self-rated measure of depressive symptom severity in the past two weeks. Each 
of the nine items is rated on a Likert scale, ranging from 0 (not at all) to 3 (nearly every day), 
and summed for a total score between 0 (no symptoms) to 27 (most severe) 38. The 
standardized cut-off scores are ≥5, 10, 15, and 20 for mild, moderate, moderate-severe, and 
severe symptoms, respectively. The PHQ-9 will be administered at baseline, and weeks 2, 4, 
and 8 visits.  
 
Perceived Deficits Questionnaire, 20-item (PDQ-20) 
The PDQ-20 is a self-report measure originally developed for the assessment of cognitive 
impairment in the past two weeks for multiple sclerosis 39. It is a 20-item questionnaire that 
generates 4 subscale scores (attention/concentration, retrospective memory, prospective 
memory, and planning/organization), and a total score which is the sum of the scores for the 20 
items.  Each item is rated on a 5-point scale ranging from 0 (never) to 5 (almost always). The 
combined subscales yield a total score ranging from 0 to 80, with a higher score indicating 
greater perceived cognitive impairment. The PDQ-20 will be administered at baseline, and 
weeks 2, 4, and 8 visits.  
 
Snaith-Hamilton Pleasure Scale (SHAPS) 
The SHAPS is a self-report measure designed to assess the degree to which a person is able 
to experience pleasure or the anticipation of a pleasurable experience 40. It includes 14 items 
involving four domains of hedonic experience: interest/pastimes, social interaction, sensory 
experience, and food/drink. Each item has four possible responses: strongly disagree, disagree, 
agree, or strongly agree. For each item, a score of 2 or less constitutes a “normal” score, while 
an “abnormal” score is defined as 3 or more, and the final score ranges from 0 to 14 41. The 
SHAPS will be administered at baseline, and weeks 2, 4, and 8 visits.  
 
Generalized Anxiety Disorder Scale, 7-item (GAD-7) 
The GAD-7 is useful in primary care and mental health settings as a screening tool and 
symptom severity measure for the seven most common anxiety disorders 42. Participants 
choose one of 4 severity scores (i.e., 0: not at all, 1: several days, 2: more than half the days, 3: 
nearly every day) associated with problems related to the common anxiety disorders and then 
indicate the degree to which these problems caused functional and/or social difficulties over the 
past two weeks. Scores are determined by calculating the values for each column. The 
minimum score is 0 and the maximum score is 32, where higher scores indicate worse anxiety.  
The GAD-7 will be administered at baseline, and weeks 2, 4, and 8 visits.  
 
EQ-5D, 5-level (EQ-5D-5L) 
The EQ-5D is a standardized measure of health status for clinical and economic appraisal that 
was developed by the EuroQol Group. The 5-level version of the EQ-5D (i.e., EQ-5D-5L) 
consists of a descriptive system and a visual analogue scale and has been validated in 34 
countries, including Canada 43,44. The descriptive system comprises five dimensions: mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has five 


 
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response levels: no problems, slight problems, moderate problems, severe problems, unable 
to/extreme problems, and the participant is asked to rate their present health (i.e., “your health 
today”). Responses are coded as single-digit numbers expressing the severity level selected in 
each dimension, ranging from 1 (no problems) to 5 (extreme problems). A participant’s self-
rated health is recorded on a vertical visual analogue scale (range 100 to 0), where the 
endpoints are labelled ‘The best health you can imagine’ (100) and ‘The worst health you can 
imagine’ (0). EQ-5D-5L health states can be summarized to derive how good or bad a health 
state is according to the preferences of the general population of a country/region. The EQ-5D-
5L will be administered at baseline, and weeks 2, 4, and 8 visits.  
 
 
World Health Organization Well-Being Index, 5-item (WHO-5) 
The WHO-5 is a measure of overall well-being, rated on a scale of 0 to 25, with higher scores 
denoting higher quality of life in the past two weeks 45. There are five items, each rated on a 
five-point Likert scale (5-All the time to 0-At no time). A score below 13 denotes poor wellbeing. 
A ≥10% difference denotes a significant change. The WHO-5 will be administered at baseline, 
and weeks 2, 4, and 8 visits.  
 
Fatigue Severity Scale (FSS) 
The Fatigue Severity Scale (FSS) is a self-rated 9-item measure used to evaluate the impact of 
fatigue within the last week 46. Responses to the FSS are based on the past week and each 
statement may be rated from a scale of 1 to 7 where 1 represents “disagree” and 7 represents 
“agree”. The minimum score that can be achieved from this scale is 9, and the maximum is 63. 
A total score of 36 or more suggests the presence of fatigue.The FSS will be administered at 
baseline, and weeks 2, 4, and 8 visits.  
 
Behaviour Inhibition System/Behavioural Activation System (BIS/BAS) 
The behaviour inhibition system (BIS)/ behavioural activation system (BAS) is a 24-item self-
report questionnaire 47This questionnaire assesses aversion to threat as well as reward-seeking 
behaviour. Items are based on a 4-point Likert scale ranging from 1 (i.e, very true for me) to 4 
(very false for me). Items 1, 6, 10, 13, 15, 18 and 20 represent BIS (i.e., punishment sensitivity 
scale). Items 3, 5, 11, 14 and 19 represent the BAS Reward Responsiveness. Items 2, 7, 9 and 
17 represent BAS drive (i.e., motivation and pursuit to achieve goals). Items 4, 8, 12 and 16 
represent BAS Fun Seeking (i.e., to seek new reward as well as obtain it spontaneously). 
BIS/BAS scores may be calculated based on the sum of each subsection.The BIS/BAS will be 
administered at baseline, and weeks 2, 4, and 8 visits.  
 
International Physical Activity Questionnaire (IPAQ) 
The International Physical Activity Questionnaire (IPAQ) is a 7-item scale that measures various 
intensities of physical activity as well as sitting time based on the past 7 days 48. The minimum 
number of days is 0 and the maximum number of days is 7. The IPAQ is administered by 
research staff at baseline, week 4 and week8 visits.  
 


 
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Post-COVID-19 Functional Status Scale (PCFS) 
The Post-COVID-19 Functional Status (PCFS) scale assesses present functional ability (i.e., “in 
your current daily life”) as it relates to daily activities (including work and/or school) 49. The 
PCFS is based on a grading system wherein the lowest grade 0 indicates no 
limitations/symptoms and the highest grade 4 represents the most limitations. The PCFS  will be 
administered at baseline, and weeks 2, 4, and 8 visits.  
 
Effort-Expenditure for Rewards Task (EEfRT) 
The Effort-Expenditure for Rewards Task (EEfRT) is a multi-trial task that measures reward and 
motivation 50. Participants are given an opportunity to earn a monetary reward based on 
successful completion of a task under various reward probabilities. In each trial, participants 
may choose to complete either the “easy task” or “hard task”. To complete the “easy task”, the 
participant must use their dominant index finger and press the space bar 30 times within 7 
seconds. To complete the “hard task”, the participant must use their non-dominant little fingers 
and press the bar 100 times within 21 seconds. The value associated with the “easy task” is $1 
while the value associated with the “hard task” may vary from $1.24-$4.30. However, successful 
completion of the task does not guarantee delivery of the monetary reward. More specifically, a 
probability is applied to the each trial and the probability varies from trial to trial. . This 
probability and the monetary value associated with a particular trial’s “easy” and “hard” tasks is 
presented to the participant so they may make an informed decision as to which task they would 
like to complete. The EEfRT will be administered at baseline and week 8 visit. Participants are 
notified before they start the EEfRT task that they will be awarded the entire monetary value 
they earn from completing this task. 
 
fMRI 
Individuals who participate in the fMRI will complete a cognitive task (e.g., EEfRT, TMT A/B) to 
obtain various functional, physiological and anatomical measurements. This is a secondary 
measure in this study and the data will be used for various exploratory analyses. Analyses may 
include standard anatomical examination, magnetic resonance spectroscopy (MRS) to measure 
brain chemistry; diffusion tensor imaging (DTI) to measure the electrical connections between 
neurons and arterial spin labelling (ASL) to measure blood flow in the small vessels of the brain.  
 
Exploratory Blood Analyses 
Plasma samples will be collected and stored for exploratory analyses. Please see above 
“Baseline (Visit 1)” for further description of the procedure.   
   
Safety Assessments 
Clinical Laboratory Tests 
Blood samples will be obtained at baseline for routine laboratory test:  
●   Haematology: complete blood count (CBC) 
●   Biochemistry: hemoglobin A1c (HbA1C), Sodium, Potassium, Lipid Assessment 
(includes cholesterol, HDL-C, Triglycerides, calculated LDL-C & Chol/HDL-C ratio) 
●  Other tests: Chloride, Bicarbonate, C-reactive peptide (CRP), erythrocyte 
sedimentation rate (ESR), estimated glomerular filtration rate (EGFR) 


 
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● hCG pregnancy screen (as applicable)  
 
A urine pregnancy test will be administered if no hCG pregnancy screen has been conducted.  
  
In the event of an unexplained clinically significant abnormal laboratory test value, the test 
should be repeated and will be followed up until it has returned to the normal range and/or an 
adequate explanation of the abnormality is found. 
 
Adverse Events  
All AEs occurring after the participant signs the ICF and up to the last study event will be 
recorded. Any unresolved AEs that are ongoing at the end of the study will be followed until 
resolution or no longer considered clinically significant by the investigator. 
 
Other Assessment Instruments  
 
Mini International Neuropsychiatric Interview Version 7.0.2 (M.I.N.I. Version 7.0.2) 
The MINI was designed as a brief structured interview for the major Axis I psychiatric disorders 
in DSM-5 and International Classification of Diseases-10. Validation and reliability studies have 
been done comparing the MINI to the Structured Clinical Interview for DSM-5 Patient Edition 
and the Composite International Diagnostic Interview (a structured interview developed by the 
World Health Organization). Version 7.0.2 of the MINI will be used for this study. The results of 
these studies show that the MINI has similar reliability and validity properties, but can be 
administered in a much shorter period (mean 18.7 ± 11.6 min, median 15 min) than the above 
referenced instruments. It can be used by clinicians after a brief training session. At screening, 
participants will be assessed for MDD and BD, as documented by DSM-5 criteria, and the lack 
of other psychiatric diagnoses will be confirmed by use of the MINI.  
 
Montreal Cognitive Assessment (MoCA) 
The MoCA is a 10-minute cognitive screening tool designed to detect mild cognitive impairment 
51. The MoCA evaluates short-term memory recall, visuospatial abilities, executive functioning, 
attention, concentration, and working memory, language, and orientation to time and place. It is 
a one-page 30-point test. In clinical practice, patients screened and found to have a MoCA 
score over 26 would be extremely unlikely to meet clinical and neuropsychological criteria for 
MCI even after extensive evaluation. The MoCA demonstrates high test-retest reliability, and 
good internal consistency, and there is a close correlation between MoCA and MMSE scores. 
Version November 7, 2004 will be administered by clinicians who have completed the official 
MoCA training and certification (https://www.mocatest.org/training-certification/). At baseline in-
person visits, participants will be assessed for mild cognitive impairment (operationalized as a 
MoCA score <26). 
 
Stanford Expectations of Treatment Scale (SETS) 
The SETS is a self-report tool designed to measure patient outcome expectancy in clinical trials 
52. The six-item SETS contains two subscales: positive expectancy (α = 0.81–0.88) and 
negative expectancy (α = 0.81–0.86). Each of the six items includes 7 selection options: 
strongly disagree, moderately disagree, slightly disagree, neither agree nor disagree, slightly 


 
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agree, moderately agree, strongly agree. The positive and negative subscales demonstrate 
strong internal reliability and are able to predict post treatment response. Most participants are 
able to complete the SETS in approximately 1 min. The SETS  will be administered at baseline 
visits.  
Study Site 
The study will be conducted at the Brain and Cognition Foundation (BCDF) main site in Toronto 
(77 Bloor St. West, Toronto, ON, M5S 1M2). BCDF is a non-profit organization engaged in 
research and educational activities as it relates to brain health and disease, including but not 
limited to studies in persons with mood disorders, as well as persons who are at-risk for mood 
disorders. BCDF conducts both proof-of-mechanism, as well as phase 1-3 clinical trials and is 
one of the most active clinical research organizations in the world based on bibliometrics. Study 
medication and placebo will be stored in a secured/locked cabinet and office at BCDF and 
medication will be dispensed by research staff per instruction/prescription of the study 
physician.  
 
The study physician will be based out of the medical clinic at CRTCE/KJK HealthPlex in 
Mississauga. As part of participants' ongoing clinical monitoring and care, all participants will 
have a medical file opened for them at CRTCE/KJK HealthPlex. The study physician evaluating 
the participant will be documenting the visits in the participant’s medical chart at CRTCE/KJK 
HealthPlex. The majority of the study visits with the study physician will be conducted remotely. 
However, in-person visits with the study physician may be scheduled at CRTCE/KJK HealthPlex 
upon the request of the participant or the study physician.  
 
Participants will complete blood draws for clinical and exploratory blood analyses at a local 
laboratory near the BCDF office in Toronto. Exploratory blood samples will be stored at the 
Biospecimen Repository and Processing Lab (Lunenfeld-Tanenbaum Research Institute, Sinai 
Health). Please see “Baseline (Visit 1)” for more details.  
 
fMRI scans are completed at an external institution (e.g. Sunnybrook Health Sciences Centre, 
University of Toronto). The research staff will inform participants where these scans will be 
taking place. 
 
Remote Visits 
Due to the ongoing COVID-19 pandemic, participants may choose to participate in the study 
completely remotely. Study visits will be conducted over online (e.g. Zoom) and telephone 
platforms. Visits with the study physician may be done over the secure Ontario TeleNetwork 
(OTN) or telephone. Participants will be mailed the study medication. Anthropometrics (e.g. 
height and weight) will be self-reported by participants. Participants will be mailed or emailed a 
lab requisition form to complete standard clinical blood tests at their local blood lab. Female 
participants will be asked to provide a urine or blood sample to confirm non-pregnancy. Female 
participants may also be mailed a home pregnancy test. 
 
Study Flow 


 
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Conditions for Withdrawal From the Study 
Premature Discontinuation 
If participation in the study is terminated prematurely for any reason, the reason for such early 
termination should be documented. The reason for any early termination should be recorded, 
providing as much information as possible.  
The reason for early termination can be selected from as follows: 
● Screen Failure: Participant does not qualify to participate in the study. 
● Lack of efficacy (e.g., increased suicidality). 
● Adverse Event: Clinical or laboratory events occurred that, in the medical judgment of 
the investigator for the best interest of the participant, are grounds for discontinuation. 
This includes serious and non-serious AEs regardless of relation to study medication. 
● Death: The participant died.    
● Withdrawal of Consent: The participant desired to withdraw from further participation in 
the study in the absence of an investigator-determined medical need to withdraw. If the 
participant gave a reason for withdrawing, it should be recorded in the eCRF.   
● Protocol Violation: The participant’s findings or conduct failed to meet the protocol entry 
criteria or failed to adhere to the protocol requirements (e.g., drug non-compliance, 
failure to return for a defined number of visits, becoming pregnant during trial). The 
violation necessitated early discontinuation from the study.   
● Lost to Follow-Up: The participant stopped coming for visits and study personnel were 
unable to contact the participant.   


 
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● Non-compliance: The participant was non-compliant with study visits or procedures.   
● Other: The participant was discontinued for a reason other than those listed above. 
Withdrawal Procedures and Next Steps 
All data outlined in Table 1 will be collected for all participants up until and including the time of 
withdrawal from the study. Recruitment will occur for this study on an ongoing basis until 200 
participants are recruited and have completed the study. Participants withdrawn from the study 
will follow the outlined “Transition to Standard Care” and “Medication Discontinuation Process” 
outlined below.  
Participant Compensation 
Compensation for In-Person Participants 
Participants will receive $125 CAD at week 2 visits, $125 at week 4 visits and $250 at week 8 
visit. Participants may also choose to receive the full $500 at the end of the study (week 8). 
Participants who complete the EEfRT task will be awarded their earnings from this task in 
addition to the $500. The EEfRT may also be administered as a stand alone assessment (i.e., 
outside of fMRI) or as part of the fMRI assessment. Participants who complete the EEfRT will be 
compensated with what they earn from this task in addition to the $500. Participants that 
complete exploratory blood work will also be compensated $50.  
 
Compensation for Remote Participants 
Participants will receive $31.25 CAD at week 2 visits, $31.25 at week 4 visits and $62.50 CAD 
at week 8 visit. Participants may also choose to receive the full $250 at the end of the study 
(week 8).  
Study Medication: Vortioxetine 
AGE: 18-64 
Participants 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.  
AGE: >65 
Per product monograph, participants 65+ 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. 
Age: 65 
Individuals aged 65 may start at 5mg or 10mg on days 1-14, and this dose may be titrated to 
10mg or 20mg, respectively, at the start of week 3 based on the recommendation of the study 
physician. 
Vortioxetine will be encapsulated in a capsule shell made of Capsugel® empty hard gelatin 
capsule (non-porcine / pure-bovine origin). Colorant: Swedish Orange OpC307. Size: AA. 


 
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Excipients: Gelatin, Red Iron Oxide, Titanium Dioxide. The filler used for both the active capsule 
with vortioxetine and the entire placebo capsule is Capsulac® 60 Lactose Monohydrate 
(Ph.Eur/USP-NF/JP). 
Individuals aged 65 may start at 5mg or 10mg on days 1-14, and this dose may be titrated to 
10mg or 20mg, respectively, at the start of week 3 based on the recommendation of the study 
physician. 
Side effects 
● Serotonin Syndrome has been reported with serotonergic antidepressants (SSRIs, SNRIs, 
and others), including with vortioxetine both when taken alone, but especially when 
coadministered with other serotonergic agents (including triptans, tricyclic antidepressants, 
fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort). 
● Treatment with serotonergic antidepressants (SSRIs, SNRIs, and others) may increase the 
risk of abnormal bleeding. Patients should be cautioned about the increased risk of bleeding 
when Vortioxetine is coadministered with nonsteroidal anti-inflammatory drugs (NSAIDs), 
aspirin, or other drugs that affect coagulation.  
● Activation of Mania/Hypomania can occur with antidepressant treatment. 
● Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated 
anatomically narrow angles treated with antidepressants. 
● Hyponatremia can occur in association with the syndrome of inappropriate antidiuretic 
hormone secretion (SIADH). 
Most Common 
● Gastrointestinal adverse events; including nausea, vomiting, constipation/diarrhea. 
Highest incidence occurs during the first week of treatment: 21-32% 
● Sexual dysfunction: 14-34% 
Less Common: 1-10% 
● Dry mouth 
● Dyspepsia (discomfort of the abdomen) 
● Dizziness 
● Somnolence/sedation 
● Fatigue 
● Insomnia 
● Abnormal dreams 
● Hyperhidrosis (increase sweating) 
● Arthralgia (joint pain) 
● Decreased appetite 
● Itchy skin 
● Nasopharyngitis 
 
 
Rare: Less than 1% 
● Nervous system disorders 
● Skin and subcutaneous tissue disorders 
● Psychiatric disorders 
● Abnormal bleeding  


 
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● Clinical worsening or suicide risk  
 
Post-Market Adverse Reactions 
The following adverse events have been identified during post-approval use of Vortioxetine. 
These events are reported voluntarily from a population of uncertain size, and it is not possible 
to reliably estimate their frequency or establish a causal relationship to drug exposure. 
● Hyperprolactinaemia 
● Acute pancreatitis 
● Anaphylactic reaction 
● Serotonin syndrome, headache 
● Agitation, aggression 
● Angioedema 
● Hemorrhage (including contusion, ecchymosis, epistaxis, gastrointestinal or vaginal 
hemorrhage) 
Please see product monograph for full details.  
Contraindications 
Hypersensitivity to vortioxetine or any components of the formulation. Angioedema has 
been reported in patients treated with vortioxetine. The use of monoamine oxidase inhibitors 
(MAOI) intended to treat psychiatric disorders with vortioxetine or within 21 days of stopping 
treatment with vortioxetine is contraindicated because of an increased risk of serotonin 
syndrome. The use of vortioxetine within 14 days of stopping an MAOI intended to treat 
psychiatric disorders is also contraindicated.  
Starting vortioxetine in a patient who is being treated with MAOIs or antibiotics such as linezolid 
or 
intravenous methylene blue is also contraindicated because of an increased risk of serotonin 
syndrome. 
Storage 
Medication will be stored at room temperature in a locked cabinet and office space at BCDF (77 
Bloor Street West, Suite 600, Toronto, ON, M5S 1M2). 
Transition to Standard of Care 
Patients will be informed of the transition to standard of care procedures (outlined here) post 
study prior to providing consent to participate in the study. These procedures will also be 
outlined in writing in the patient consent form itself.  
Upon completing the 8-week course of vortioxetine, if patients benefit from this drug, they will be 
encouraged to continue the treatment with their most responsible physician (MRP). Patients will 
be notified prior to study consent that not all drug plans will cover the cost of vortioxetine. 
Should patients wish to continue to use this drug post-study when they do not have coverage, 
they will be personally responsible for the costs.  
If patients do experience side effects during the study, the study physician will make a 
recommendation regarding the discontinuation or dose reduction of the medication for the 


 
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remainder of the study. If participants do not experience any improvement upon study 
completion in mood or cognition, the medication will be gradually discontinued over a two-week 
period upon study completion (end of week 8). Participants will take half of their final dose of 
vortioxetine during the first week post-study and no medication during the second week of 
discontinuation. Participants will be provided with one week worth of medication for this 
discontinuation process but will not be provided any further supply thereafter.  
Vortioxetine discontinuation process 
At the end of week 8, patients will be seen by the study physician and provided with half of 
current vortioxetine dosage for a period of 1 week. This is in keeping with the product insert, 
although vortioxetine does not cause discontinuation syndrome. During the second week, 
patients will not be on medication and will be seen by the study physician at the end of two 
weeks, to ensure that there are no risks or adverse events during this time period. This visit with 
the clinician is post-study, and not part of the study visits. Patients are encouraged to contact 
the study team in the event that they would like to be scheduled with the physician earlier.  
Data Handling 
Personal Data Protection 
All data collection material will be de-identified. Participant records will be distinguished using 
participant identification (PID) numbers. 
Data Collection and Retention 
The majority of data will be collected electronically through the secure RedCap platform. 
Participants will also sign the consent form via the RedCap platform after a thorough discussion 
with research staff during the in-person screening visit. Participants will receive an electronic 
copy of their consent form via email. Participants may also receive a printed copy of the consent 
form if this is preferred. Records and documents pertaining to the conduct of the study as well 
as all data collected as part of the study will be retained in a secure place for 25 years in 
accordance with Health Canada regulations. All data collected throughout the study will be kept 
with membership of the BCDF for 25 years. Data collected as hard copies (e.g. paper format) 
may be digitized and stored electronically, after which the hard copies will be destroyed (even 
before the 25 years). 
Participants’ de-identified plasma samples (labelled with participant ID) will be stored in a -80 
degrees Celsius freezer for a maximum of 15 years from the time of collection. Participants may 
choose to withdraw their samples at any time. 
Participant Protection 
Participants will not be placed at any risk as a result of the study. Information obtained will be 
maintained in a secure and confidential fashion. No participant will be coerced and/or placed 
under duress to complete study procedures. 
Adverse Events 
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 


 
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pharmaceutical product, whether or not considered causally related to the product. An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, 
electrocardiogram). In clinical studies, an AE can include an undesirable medical condition 
occurring at any time, including run-in or washout periods, even if no study treatment has been 
administered. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication. Follow-up of 
adverse events should be based upon the clinical judgement of the investigator. 
Assessment of Intensity 
Each AE will be classified according to the following criteria: 
●     Mild: The AE does not interfere in a significant manner with the participant’s normal 
level of functioning. 
●     Moderate: The AE produces some impairment of functioning, but is not hazardous to 
the participant’s health. 
●     Severe: The AE produces significant impairment of functioning or incapacitation and 
is a definite hazard to the participant’s health. 
 When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the experience should be noted. If the intensity category changes over several 
days, those changes should be recorded separately (with distinct onset dates). 
Severity versus Seriousness 
It is important to distinguish between serious and severe AEs.  Severity is used to describe the 
intensity of a specific event while the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This is not the same as "seriousness," which is based 
on participant/event outcome at the time of the event.  An AE of severe intensity need not 
necessarily be considered serious.  For example, nausea that persists for several hours may be 
considered severe nausea, but not an SAE.  On the other hand, a stroke that results in only a 
limited degree of disability may be considered a mild stroke but would be an SAE. Symptoms 
associated with overdose should be reported as AEs. For further information regarding 
overdose, see section.  
Recordings of Adverse Events 
Adverse events will be collected from baseline to endpoint. At each visit, subjects will be asked 
if they have experienced any health problems or side effects since the previous visit. All AEs will 
be recorded appropriately, whether or not considered related to the investigational product. This 
will include AEs spontaneously reported by the patient and/or observed by members of the 
research team as well as AEs reported in response to a direct question (e.g., “Have you 
experienced any health problems or side-effects since your last visit?”).  
 
For each AE, the following parameters will be described: 
● Discovery (i.e., spontaneous or solicited) 


 
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● Start date 
● Stop date or ongoing 
● Action taken with regards to investigational product 
● Outcome if the AE caused the patient to discontinue the investigational product 
● A statement if the AE fulfills the criteria for a SAE or not 
● The investigator’s assessment of the causal relationship between the event and the 
investigational product 
● Intensity of the AE 
    o   Mild (awareness of sign or symptom, but easily tolerated) 
    o   Moderate (discomfort sufficient to cause interference with normal activities) 
    o   Severe (incapacitating, with inability to perform normal activities) 
● Resolution  
Assessment of Causality 
Each AE will be assessed as to its relationship to the IP, based on the following criteria. 
Although the attribution by the investigator will be collected for reported events, for analytic 
purposes a temporal association with the use of the IP will be assumed sufficient for at least 
plausible association. 
●     Not related: No causal relationship exists between the IP and the AE, but an obvious 
alternative cause exists, eg, the participant’s underlying medical condition or 
concomitant therapy. 
●     Possibly related: A connection with the administration of the IP appears unlikely, but 
cannot be ruled out with certainty. An AE may be considered possibly related if or 
when it meets 2 of the following criteria: (1) it follows a reasonable temporal 
sequence from administration of the IP; (2) it could not readily have been produced 
by the participant’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the participant; or (3) it follows a known pattern of response 
to the IP. 
●     Related: There is a reasonable/plausible possibility that the AE may have been 
caused by the IP. 
 When assessing the relationship to the IP, the following criteria will be considered: 
●     Known class effect 
●     Biological plausibility 
●     Lack of alternative explanation—concomitant drug or disease 
 
Action Taken Regarding Investigational Product 
Dose modifications of IP (ie, dose not changed, drug withdrawn, drug interrupted, or dose 
increased). 
●     Not Applicable: Participant died, study treatment had been completed prior to 
reaction/event, or reaction/event occurred prior to start of treatment. 
Other Action Taken for Event 


 
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25 
 
●     1 = None (ie, no treatment was required) 
●     2 = Medication required (ie, prescription and/or OTC medication was required to treat 
the AE) 
●     3 = Hospitalisation or prolongation of hospitalisation required (ie, hospitalisation was 
required or prolonged because of the AE, whether medication was required) 
●     4 = Other 
Adverse Event Outcome 
●     1 = Recovered/Resolved (ie, the participant fully recovered from the AE with no 
residual effect observed) 
●     2 = Recovering/Resolving (ie, the AE improved but has not fully resolved) 
●     3 = Not Recovered/Not Resolved (ie, the AE itself is still present and observable) 
●     4 = Recovered/Resolved with Sequelae (ie, the residual effects of the AE are still 
present and observable, including sequelae/residual effects) 
●     5 = Fatal (ie, ‘fatal’ should be used when death is a direct outcome of the AE) 
●     6 = Unknown 
Clinical Laboratory Changes 
Any abnormality in a laboratory value that is new in onset or which has worsened in severity or 
frequency from the baseline condition and meets 1 of the following criteria will be recorded on 
the AE pages of the eCRF: 
●     Requires therapeutic intervention or diagnostic tests 
●     Leads to discontinuation of IP 
●     Has accompanying or inducing symptoms or signs 
●     Is judged by the investigator as clinically significant 
Combined elevations of aminotransferases and bilirubin, either serious or nonserious, and 
whether causally related, meeting the criteria of a potential Hy’s Law case (total bilirubin level ≥ 
2 × upper limit of normal [ULN] with simultaneous ALT or AST ≥ 3 × ULN) should always be 
reported to the sponsor as soon as possible following the procedures outlined in Section 10.2 
for SAE reporting, with the investigator’s assessment of seriousness, causality, and a detailed 
narrative. 
Overdose 
Any instance of overdose (suspected or confirmed) must be fully documented as an AE or SAE 
if it meets the SAE criteria. Details of any signs or symptoms and their management should be 
recorded including details of any antidote(s) administered. 
Adverse Event Follow-up 
All AEs will be followed until resolved or stable and the outcome documented on the eCRF. If 
the investigator detects an AE in a study participant after the last scheduled follow-up visit and 


 
Version 9: May 30th, 2022 
 
26 
 
considers the event possibly related or related to prior study treatment, the investigator will 
document it. 
Serious Adverse Events (SAE)/Serious Adverse Drug 
Reaction (SADR) 
Definition: A serious adverse event (SAE)/Serious Adverse Drug Reaction (SADR) is an AE 
occurring during any study phase (i.e., run-in, treatment, washout, follow-up), and at any 
procedure, that fulfills one or more of the following criteria: 
● Results in death 
● Is immediately life-threatening 
● Requires inpatient hospitalization or prolongation of existing hospitalization 
● Results in persistent or significant disability or incapability 
● Is a congenital abnormality or birth defect 
● Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above 
Any serious, untoward event that may occur subsequent to the reporting period that the 
investigator assessed as related to IP should also be reported and managed as an SAE. The 
investigator should follow participants with AEs until the event has resolved or the condition has 
stabilized. In case of unresolved AEs, including significant abnormal clinical laboratory values at 
the end of study assessment, these events will be followed until resolution or until they become 
clinically not relevant. Disability/incapacitating: An AE is incapacitating or disabling if the 
experience results in a substantial and/or permanent disruption of the participant's ability to 
carry out normal life functions. 
The causality of SAEs/SADRs (i.e., their relationship to study treatment) will be assessed by the 
investigator(s). Note that SAEs/SADRs that could be associated with any study procedure 
should also be reported. For such events the causal relationship is implied as “yes”. 
Serious unexpected adverse drug reaction (SUADR) Definition: means a serious 
adverse drug reaction (SADR) that is not identified in nature, severity or frequency in the risk 
information set out in the investigator's brochure or on the label of the drug. 
Reporting of SAEs/SADRs/SUADRs 
All SAEs/SADRs/SUADRs should be reported to the sponsor immediately. The immediate 
reports should be followed promptly by detailed, written reports. The immediate and follow-up 
reports should identify subjects by unique code numbers assigned to the trial subjects rather 
than by the subjects' names, personal identification numbers, and/or addresses.  
The QI should comply with the applicable regulatory requirement(s) related to the reporting of 
serious unexpected adverse drug reactions to the regulatory authority(ies) and the REB. 
SAEs/SADRs: The sponsor-investigator will comply with any and all national rules and 
regulations concerning safety reporting (SADRs or SAEs as required). All SAEs/SADRs 
(according to the definition in ICH GCP) will be done by the investigator in accordance with local 
regulations and reported to the appropriate regulatory bodies.  


 
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27 
 
SUADRs: In accordance with section C.05.014 of the Regulations, it is the responsibility of a 
sponsor to inform Health Canada, in an expedited manner, of all SUADRs in respect of a drug 
during the course of a Phase I-III clinical trial, whether or not the event occurred inside or 
outside of Canada: 
a. this information must be submitted within 15 calendar days after becoming aware of 
the event if it is neither fatal nor life threatening 
b. if the event is fatal or life threatening, Health Canada must be advised of the event 
within 7 calendar days after the sponsor first became aware of it. 
In cases where the event is fatal or life threatening, the sponsor must submit a complete 
report to Health Canada within 8 calendar days after the first notification (initial report) to 
Health Canada of the event. Follow-up reports of fatal or life threatening reactions must include 
an assessment of the importance of the event and the implication of any findings, including 
relevant previous experience with the same or similar drugs. 
In addition, in keeping with ICH GCP, the sponsor should expedite reporting of all SUADRs to 
all concerned QI(s)/institution(s), the REB(s) where required (ICH E6, 5.17.1). 
Statistical analysis plan 
Data will be analyzed for a modified intent-to-treat set: the full analysis set (FAS) will comprise 
all patients who received at least one dose of study medication and had at least one valid post-
baseline assessment of the primary outcome.  
● The MMRM model will use study visit as a fixed factor and the interaction between 
treatment and visit to allow for estimation of treatment effect at specific time points. 
Additionally, the interaction term of visit and baseline to allow for time dependent 
adjustment of baseline. An unstructured covariance matrix will be used.  
 
To control for type I error, the following sequence of hierarchically ordered primary and key 
secondary end points will be used at a significance level of 0.05 1-sided for the primary 
outcome: 
● Primary endpoint: Change from baseline to week 8 between vortioxetine and placebo in 
DSST performance score 
● Secondary endpoint: Change from baseline to week 2 between vortioxetine and placebo 
in DSST performance score 
The change from baseline in DSST performance score after 8 weeks of treatment will be 
analyzed with a one-sided mixed model for repeated measures (MMRM) with treatment and 
study visits as fixed factors and baseline DSST performance as covariate. For secondary 
analyses, the change from baseline in DSST, CogState Online Cognitive Battery, PDQ-20, 
TMT-A/B, SHAPS, FSS, GAD-7, WHO-5, EQ-5D-5L, BAS, RPE, RAVLT, PCFS, EEfRT, SETS, 
QIDS-SR16, IPAQ and SDS will also be analyzed using a mixed model for repeated measures 
(MMRM) using all available data. Withdrawal rates will be compared between placebo- and 
vortioxetine-randomized participants at week 8. 
A power calculation was obtained via computer simulations on the primary outcome of 
difference in the change from baseline in DSST performance score between vortioxetine and 
placebo. Assuming an SD of 8.0 for the change from baseline in the DSST performance score 


 
Version 9: May 30th, 2022 
 
28 
 
at week 1 and a 15% dropout rate, based on previous randomized, placebo-controlled trials with 
vortioxetine, it was calculated that 100 subjects (modified per treatment group) are required to 
achieve 80% power to detect a difference of 3.1 in the change from baseline in DSST 
performance score between vortioxetine and placebo (i.e., Cohen’s d=0.38) by an MMRM with a 
1-sided significance level of p<0.05 26,53.  
The magnitude of fMRI-determined ventral striatal (including nucleus accumbens) activation 
during anticipation of gain versus no-incentive trials, as well as loss versus no-incentive trials, in 
the EEfRT task. Mean and maximum fMRI ventral striatal activation will be assessed.  
Publication Plan 
Manuscript will be prepared within two weeks of the last subject's last visit. Manuscript will be 
submitted to a high-impact peer-reviewed journal. Data from the study will also be presented at 
national and international meetings.  
Documentation 
We will be documenting the findings in the form of peer-reviewed manuscripts as well as 
posters at international meetings.  
Contract Details 
Brain and Cognition Discovery Foundation 
77 Bloor Street West, Suite 600, Toronto, ON, M5S 1M2 
 
 


 
Version 9: May 30th, 2022 
 
29 
 
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ICF_001.pdf: 
 
Brain and Cognition Discovery Foundation / Protocol Number BCDF002 
Page 1 of 20   
 
 
Roger McIntyre, MD, FRCPC 
NCT05047952 
1-Jun-2022 
 
 
PARTICIPANT INFORMATION AND CONSENT FORM  
TO PARTICIPATE IN A RESEARCH STUDY 
 
Sponsor / Study Title: 
  
Brain and Cognition Discovery Foundation / “Randomized, 
Double-Blinded, Placebo-Controlled Study Evaluating 
Vortioxetine for Cognitive Deficits in Persons with Post-
COVID-19 Condition” 
 
Protocol Number: 
 
BCDF002 
Principal Investigator: 
 
 
Dr. Roger McIntyre, MD, FRCPC 
 
Study Doctor:  
(Sub-Investigator) 
Dr. Pawel Drzadzewski, MD 
Telephone: 
 
 
647-450-8045 
911 (24-Hour) 
 
Address: 
Brain and Cognition Discovery Foundation (BCDF) 
77 Bloor Street West, Suite 600 
Toronto, ON M5S 1M2  
 
 
Introduction 
You are being asked to take part in a research study. Before agreeing to participate in this study, 
it is important that you read and understand the following explanation of the proposed study 
procedures. The following information describes the purpose and procedures of this study. It also 
describes your right to refuse to participate or withdraw from the study at any time. In order to 
decide whether you wish to participate in this research study, you should understand enough 
about its risks and benefits to be able to make an informed decision. This is known as the 
informed consent process.  
 
Please ask the study team to explain any words you do not understand before signing and dating 
this consent form. Make sure all your questions have been answered to your satisfaction before 
signing and dating this document.  


 
Brain and Cognition Discovery Foundation / Protocol Number BCDF002 
Page 2 of 20   
 
 
Roger McIntyre, MD, FRCPC 
NCT05047952 
1-Jun-2022 
 
 
An investigator on this study is being paid by Lundbeck, the company supplying the study drug, 
for activities that are not part of the study. These activities may include, for instance, consulting, 
serving on advisory boards, or giving speeches. Please speak with your study doctor if you have 
questions about this. 
 
Background 
You have been asked to take part in this research study because you are currently suffering from 
post-COVID-19 condition.  
 
According to the World Health Organization (WHO), 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 (feeling tired), 
shortness of breath, and cognitive dysfunction (“brain fog”), 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.  
 
Purpose 
The purpose of this study is to evaluate the efficacy of vortioxetine (study drug) in improving 
cognition among individuals with post-COVID-19 condition. “Cognition” refers to intellectual 
functions such as thinking, understanding, learning, and remembering.  
 
Vortioxetine is an antidepressant medication approved by Health Canada for the treatment of 
major depressive disorder (MDD). In addition, vortioxetine has been reported to have a 
beneficial effect on cognitive areas such as executive function, attention/speed of processing, and 
memory, that are commonly affected negatively by MDD. Vortioxetine is recognized by Health 
Authorities in the European Union and many other countries as having a benefit on cognitive 
dysfunction (loss of intellectual functions) in patients with MDD. The use of vortioxetine in this 
study is investigational. An investigational use is one that is not approved by Health Canada. 
Half of the study participants (100 participants) will be randomly chosen (like the flip of a coin) 
to receive vortioxetine 10 mg/day for the first two weeks of the study treatment period. This dose 
will be increased to 20 mg/day from Week 2 to 8 in consultation with the study doctor. The other 
half of the participants (100 participants) will receive placebo (medically inactive substance) for 
the duration of 8 weeks. Your participation in this study will last approximately 10 weeks. 
 
Participants over 65 years of age will receive vortioxetine 5 mg/day for the first 2 weeks, then 
transitioned to vortioxetine 10 mg/day for the remaining 6 weeks of the study.  
 
You should not be enrolled in this study if you have/are: 
1. Current symptoms due to a diagnosis of major depressive disorder or bipolar disorder. 


 
Brain and Cognition Discovery Foundation / Protocol Number BCDF002 
Page 3 of 20   
 
 
Roger McIntyre, MD, FRCPC 
NCT05047952 
1-Jun-2022 
 
2. Pre-existing conditions that may cause cognitive impairment, or symptoms similar to 
those seen in post-COVID-19 condition (for example, ADHD [attention-
deficit/hyperactivity disorder], major neurocognitive disorder, schizophrenia). 
3. Not able to provide written, informed consent. 
4. Not able to follow study procedures.  
5. Known intolerance to vortioxetine and/or prior use of vortioxetine with demonstrated 
efficacy. 
6. Previous hypersensitivity reaction to vortioxetine or any components of the formulation. 
Angioedema (swelling of the deeper layers of the skin) has been reported in patients 
treated with vortioxetine.  
7. Currently taking antidepressants or have in the past 4 weeks prior to study start. If you 
are currently taking antidepressant(s), you will be required to be off the antidepressant(s) 
for 2-4 weeks prior to the start of the study. In some cases and upon the discretion of the 
study doctor, you may continue to take your antidepressant(s) during your participation in 
the study. Combining vortioxetine with another antidepressant would be considered 
investigational, as the safety and efficacy of this combination is unknown. 
8. Current alcohol or substance use disorder. 
9. Taking other medications for cognitive dysfunction (for example, psychostimulants). 
10. Taking any medication for a general medical disorder that in the opinion of the study 
doctor may affect cognitive function. 
11. Used benzodiazepines within 12 hours of cognitive assessments. 
12. Drank alcohol within 8 hours of cognitive assessments. 
13. A physical, cognitive, or language impairment that might affect cognitive assessments. 
14. A reading disability or dyslexia and clinically significant learning disorder. 
15. Had electroconvulsive therapy (ECT) in the last 6 months. 
16. A history of moderate or severe head trauma (for example, loss of consciousness for less 
than 1 hour), other neurological disorders, or medical conditions that in the opinion of the 
study doctor are likely to affect the central nervous system. 
17. Pregnant and/or breastfeeding. 
18. Received investigational agents as part of a separate study within 30 days of the 
screening visit. 
19. Actively suicidal/presence of suicidal ideation or evaluated as being a suicide risk. 
20. Currently receiving treatment with antidepressants, antibiotics such as linezolid, or 
intravenous methylene blue. 
21. Serotonin syndrome. 
22. Abnormal bleeding. 
23. Previous history of mania/hypomania. 
24. Angle closure glaucoma. 
25. Hyponatremia (a condition where sodium levels in the blood are lower than normal). 
26. Moderate hepatic (liver) impairment. 
27. Active seizure disorder/epilepsy, not controlled by medication.  
28. Presence of any unstable medical conditions. 
 


 
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If you are already taking other antidepressants, you may enroll in the study only upon the 
discretion of the study doctor. It is possible that vortioxetine may augment/enhance the effects of 
your current antidepressant medication. However, the safety and efficacy of the combination of 
vortioxetine and other antidepressants has not been well characterized and should be considered 
investigational.  
 
This study will be sponsored by the Brain and Cognition Discovery Foundation (BCDF). The 
BCDF is an organization based in Toronto, Ontario, Canada led by Dr. Roger S. McIntyre. 
 
This consent form is for individuals with a diagnosis of post-COVID-19 condition. 
 
Study Design 
This is an 8-week, randomized, double-blinded, placebo-controlled study. “Double-blinded” 
means neither you nor the study team will know if you are getting vortioxetine or placebo. You 
will be receiving vortioxetine or placebo daily for a period of 8 weeks. You will need to take the 
study drug daily as prescribed in order to take part in the study.  
 
You will be asked to participate in 5 study visits. As part of this study, your mood, cognition, 
functioning, overall well-being, as well as lifestyle factors will be assessed. There may be 
instances when additional visits are required to complete study procedures.  
 
*Due to the ongoing nature of the pandemic, you may choose to participate in ALL study 
visits remotely. Study visits will be conducted through online platforms (for example, 
Zoom) and/or telephone. The study drug will be mailed to you, or may be available for 
pickup at the BCDF office. You will also be mailed/emailed a blood requisition form to 
complete at your local blood lab. Female participants will be required to complete a home 
pregnancy test or provide blood/urine sample to the blood lab to confirm they are not 
pregnant.  
 
Visits with the study doctor will occur remotely, via the secure online video conference 
platform or telephone. If necessary/requested by you or study doctor, in-person visits may 
be scheduled as well.  
 
A total of approximately 200 participants will be enrolled in this study; 100 individuals will 
receive vortioxetine, and the remaining 100 individuals will receive placebo. 
 
Study Visits and Procedures 
 
Study Doctor Assessment: You will see the study doctor during the same weeks as the study 
visits with the research team for ongoing monitoring of your care. Some or all visits may be 
conducted remotely/online through a secure platform. As part of your care, a medical file will be 
opened for you at CRTCE/KJK Healthplex and the study doctor will document each visit in your 


 
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medical file at CRTCE/KJK Healthplex. Your medical records will be protected by the highest 
standards under Canadian law. 
 
Self-Report Questionnaires: You may choose to complete self-reported questionnaires during 
your visit with the research team or within 24 hours of the visit. If you choose to complete these 
questionnaires before/after the visit, you will be emailed a secure and anonymized link to the 
questionnaire.  
 
Exploratory Blood Analyses: If you are seen in-person, you may volunteer to provide a blood 
sample for exploratory analyses. The sample will be collected at a local blood lab (Mount Sinai 
Hospital), followed by processing and storage of the sample at the Biospecimen Repository and 
Processing Lab (Lunenfeld-Tanenbaum Research Institute, Sinai Health). You may also have 
blood drawn at the same time for clinical purposes at Mount Sinai Hospital. The clinical blood 
tubes will be delivered to another local lab (Dynacare, LifeLabs) for analyses. Alternatively, you 
may also have blood drawn separately for clinical analyses at a local blood lab near you - this 
will result in two separate blood draws. Blood work is done at baseline and week 8 (endpoint).  
 
Screening Visit (Visit 0) 
The following will be completed during this visit:  
● Informed consent process will be completed. 
● The study team will carry out an interview to confirm your suitability for the study.  
● Your demographics and anthropometrics will be documented, including current physical 
activity levels.  
● Medical/psychiatric and medication history will be recorded.  
● Your mood, functioning, and overall well-being will be assessed.  
● Study doctor assessment.  
 
Reminders:  
● Please do not consume any recreational substances (for example, alcohol, marijuana) 8 
hours before any study visit.  
● Some medications may be restricted within 8-10 hours of study visits.  
● Please fast (no food or drinks, except for water) for at least 8 hours prior to bloodwork 
(baseline and end-of-study visits). Only water can be consumed during the fasting period.  
 
 
Baseline (Visit 1) 
The following will be completed during this visit:  
● Anthropometrics (for example, weight, hip/waist circumference, height, blood pressure) 
and physical activity levels will be documented (will be self-reported by participants for 
remote study visits).  
● Adverse events will be recorded. 
● Study staff assessments and self-completed questionnaires about cognition, mood, and 
well-being.  


 
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● Fasting (no food or drinks, except for water for a minimum of 8 hours) bloodwork for 
exploratory and standard clinical analyses. This testing is done for research and clinical 
purposes. Approximately 20 mL of blood will be drawn in 4-5 blood tubes. You are 
welcome to request a copy of your clinical results from your study doctor.  
● Optional functional magnetic resonance imaging (fMRI) participation for select 
participants (more information below). 
● Receive study treatment (vortioxetine [10 mg] or placebo) after assessment by a study 
doctor. For participants over 65 years of age, the starting dose is 5 mg for two weeks.  
● Pregnancy test (urine or blood).  
● The research staff will dispense the study drug to you.  
 
Week 2 (Visit 2)  
The following will be completed during this visit:  
● Anthropometrics (for example, weight, hip/waist circumference, height, blood pressure) 
and physical activity levels will be documented (will be self-reported by participants for 
remote study visits). 
● Study staff assessments and self-completed questionnaires about cognition, mood, and 
well-being.  
● Adverse events. 
● Study treatment dosage increased to 20 mg by the study doctor. For participants over 65 
years of age, the dosage will be increased to 10 mg by the study doctor. The research 
staff will dispense the study drug to you per the study doctor’s recommendations.  
 
Week 4 (Visit 3) 
The following will be completed during this visit:  
● Anthropometrics (for example, weight, hip/waist circumference, height, blood pressure) 
and physical activity levels will be documented (will be self-reported by participants for 
remote study visits).  
● Study staff assessments and self-completed questionnaires about cognition, mood, and 
well-being.  
● Adverse events. 
● Study doctor assessment.  
 
Week 8 (Visit 4)  
The following will be completed during this visit:  
● Anthropometrics (for example, weight, hip/waist circumference, height, blood pressure) 
and physical activity levels will be documented (will be self-reported by participants for 
remote study visits).  
● Study staff assessments and self-completed questionnaires about cognition, mood, and 
well-being.  
● Optional fMRI participation. You will be asked to complete a brief cognitive task during 
the fMRI imaging.  


 
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● Adverse events.  
● Fasting (minimum of 8 hours) bloodwork for exploratory and standard biomarker and 
testing. This testing is done for research and clinical purposes. Approximately 20 mL of 
blood will be drawn in 4-5 blood tubes. You are welcome to request a copy of your 
clinical results from your study doctor.  
● Study doctor assessment.  
 
fMRI Participation (Optional) 
 
What is an fMRI? 
Functional MRI records brain activation signals indirectly from changes in blood flow and 
oxygenation that arise from activated neurons. You will have your brain scanned while 
completing a series of neuropsychological tests. The fMRI brain scan will provide a high spatial 
resolution map of the brain areas activated during task performance and the connection between 
these activated areas. Additionally, you may be completing these same tasks outside of the fMRI 
with pen and paper. This will help us ensure that testing done during fMRI is valid. In both 
cases, a special video camera will record your eye movements to determine where you are 
looking. 
 
Why is brain imaging used in this study?  
Brain imaging is used in this study to better understand the brain measures of anatomy, 
physiology, and function in people with post-COVID-19 condition. In this study four types of 
scans will take place: MRI to obtain an anatomical image of your brain, one to measure brain 
chemistry, another one will measure the electrical connections between neurons, and the fourth 
will measure blood flow in the small vessels of the brain.  
 
 
 


 
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What can I expect if I decide to participate in the fMRI scan? 
fMRI scans are completed at an external institution (for example, Sunnybrook Health Sciences 
Centre, University of Toronto). The research staff will let you know exactly where you are going 
for the fMRI. You will be asked to participate in two scans at the start of the study (baseline) and 
at the end of the study (week 8). Please note that only a limited number of participants will be 
given the opportunity to participate in the fMRI component of the study.  
 
Prior to your fMRI scan, you will be trained on how to perform the cognitive test. Before the 
scan begins, you will be asked to remove any magnetic metals that you may be wearing (for 
example, watch, jewelry).  You will be asked to lie on a padded bed that will be moved into a 
tunnel-like machine for the fMRI scan of your brain. Because you will be inside the machine 
during the scan, you may not be able to see the technologist operating the machine or the 
investigators.  However, there is an intercom system that will allow you to talk with them at any 
time.  If you feel uncomfortable during the scan and you wish to discontinue the procedure, you 
will be taken out of the machine at your request.  
 
We will obtain a series of MRI scans, separated by short breaks, and the entire procedure will 
take approximately one hour. You should try to remain as still as possible during each scan.  
Movement will not be dangerous to you in any way, but could blur the picture of your brain.  
You will hear moderately loud knocking or beeping during the scan when the MRI machine is in 
operation.  Although you may find this to be unsettling, the machine cannot hurt you in any way. 
You will be provided with earplugs or earphones to drown out the noise, as well as foam pads to 
make you as comfortable as possible. 
 
In addition, your participation may involve additional procedures and interacting with one or 
more devices that are being designed to operate inside the MRI scanner.  These include: 
 
● wearing a specially-designed plastic “tool” that enables motion of the body to be tracked 
using a camera; 
● wearing a small number of electrodes to measure the electrical conductivity of your skin; 
● wearing a small number of electrodes to measure activation of your muscles; 
● wearing or using various devices to enable performance of behavioural tasks during fMRI 
(goggles or glasses to view video, words, or pictures; headphones to hear sounds; 
transducers to feel vibrations; buttons to make keypress responses; steering wheel and 
foot pedals for driving tasks; or a tablet to draw or make writing responses); 
● wearing virtual reality (VR) equipment (head-mounted display, data glove) to enable 
behavioural testing to be undertaken in a virtual environment similar to that of the real 
world; 
● recording video of your eye movements to determine where you are looking; 
● participating in any of these procedures in a mock, “simulated” MRI scanner, to optimize 
the experimental study plan prior to working inside the magnet. 
Who should NOT participate in fMRI imaging?  


 
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You should not participate if you have a cardiac pacemaker or any other metal in your body such 
as metal implants, aneurysm clips, pieces of shrapnel, wires, body piercings, and metal stitches 
from surgery. These materials will corrupt the fMRI measurements by producing unwanted 
signals. Dental fillings are acceptable. We will check all of these issues by having you complete 
a screening form to ensure that you can undergo MRI measurements safely and to determine 
whether you are eligible to participate. 
 
What are the risks and harms of participating in an fMRI scan? 
You may experience side effects from participating in this study. Some side effects are known 
and are listed below, but there may be other side effects that are not expected. Please inform the 
study team immediately about any side effects or study-related injuries that you experience.  
 
While all forms of diagnostic medical procedures involve some risk, the known hazards 
associated with MRI scanning are negligible. There are no known adverse effects of MRI 
scanning on biological tissues that are not fully reversed after the end of the investigation.  The 
MRI scanner operates within the US Food and Drug Administration (FDA) limits to ensure that 
even temporary effects are not severe. Some people may experience claustrophobia (5-10% 
possibility) because the magnet may feel cramped/confining and makes loud knocking sounds. 
You will be connected by intercom to an operator who can interrupt and remove you from the 
scanner at any time. In addition, some MRI scans can cause some people to feel knocking, 
tapping, or buzzing sensations in their arms or legs. These feelings are completely harmless. You 
may feel fatigued or sleepy after lying in the magnet. 
 
This MRI study was designed for research, not for medical diagnostics, and cannot rule out the 
discovery of possible brain abnormalities. There is a small possibility that your research MRI 
scans might reveal unexpected medical findings.  In this case, the study doctor may consult a 
radiologist. If the radiologist determines that further medical efforts are warranted, the study 
doctor will inform you and assist you to receive appropriate health care. The radiologist will only 
be consulted in the case of incidental findings, and will not be reviewing every scan. As these are 
research MRIs, they may not be reviewed until the end of the study or sometime thereafter. 
 
You will be told about any new information that might reasonably affect your willingness to 
continue to participate in this study as soon as the information becomes available to the study 
staff.  
 
Transition to Standard Care Upon Completing the Study 
Upon completing the 8-week study, if you benefit from this study drug, you are encouraged to 
continue the treatment with your most responsible physician (MRP). Please note that your 
private medical insurance (if any) or the public health insurance plan may not cover the cost of 
vortioxetine. Should you wish to continue to use this drug post-study where there is no coverage, 
you will be personally responsible for the costs. Please also note that the study doctor is not able 
to provide ongoing care beyond the study and is not considered the MRP at any time point.  
 


 
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If you do not experience any improvement upon study completion in mood or cognition, the 
study drug will be gradually discontinued over a two-week period upon study completion (end of 
week 8). You will take half of the final dose of vortioxetine during the first week post-study and 
no study drug during the second week of discontinuation. You will be provided with one week 
worth of study drug for this discontinuation process but will not be provided any further supply 
thereafter.  
 
Vortioxetine can be safely discontinued however, you may experience side effects such as:  
● Muscle tension 
● Rebound depression 
● Brain zaps/sensation of an electrical shock 
● Depersonalization (feelings of loss of identity) 
● Not feeling like yourself 
● Dizziness 
● Flu-like symptoms 
● Nausea and vomiting 
● Sweating 
● Headaches 
● Suicidal thoughts 
 
If you are having suicidal thoughts call the study doctor at the telephone number listed on the 
first page of this form. If you feel in crisis, you can call 911 and/or a Nationwide Suicide Hotline 
that is answered 24 hours a day with a skilled, trained counselor. One example is the Canada 
Suicide Prevention Service at 1-833-456-4566. 
 
If you experience side effects during the study, a study doctor will make a recommendation 
regarding the discontinuation or dose reduction of the study drug for the remainder of the study.  
 
Please note the study team will not know who received vortioxetine and who received placebo 
until the study is complete. You may contact the research team once the study is complete to find 
out whether you received vortioxetine or placebo.  
 
Post-Study Visit (Optional) 
You will be seen by the study doctor to monitor safe study drug discontinuation.  This visit will 
consist of the study doctor’s assessment of your overall well-being. After one post-study clinical 
visit two weeks after the end of the study, you will be asked to continue your care with your most 
responsible physician (MRP). The visit will consist of your overall well-being and management 
plan with your most responsible physician. 


 
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Schedule of Visits 
 
Screenin
g (V0) 
Baseline 
(V1) 
Week 
2 
(V2) 
Week 4 
(V3) 
Week 8 
(V4) 
Post-
Study  
Visit 
(Optional) 
Assessment with Study 
Staff/Self-Completed 
Questionnaires 
X 
X 
X 
X 
X 
 
Study Doctor Assessment  
 
X      
 
X 
X 
X 
X 
 
 
 
Fasting Blood Work  
 
X 
 
 
X 
 
Study Drug Receipt 
 
X 
X 
 
X* 
 
fMRI (optional) 
 
X 
 
 
X 
 
Approx. Total Time of Visit 
(hours)** 
2 
2 
1.5 
1 
2 
 
*Applies to participants who will not continue treatment after study. Please see “Transition to Standard Care Upon Completing the Study’ for 
more details. 
**Does not include time taken for blood work and optional fMRI scan. 
Note:  
● You will be expected to take the study drug as prescribed every day from the start to the 
end of the study (end of week 8). Please let the study team know if you have any 
questions about this.  
 
Risks Related to Being in the Study  
Taking part in this study has risks. Some of these risks we know about. There is also a possibility 
of risks we do not know about and have not been seen in humans to date. Additionally, there may 
be unknown risks to a pregnancy, embryo, or fetus if you or your female partner become 
pregnant. Please call the study doctor if you have any side effects even if you do not think it has 
anything to do with this study.  
 
The known risks associated with vortioxetine are:  
 
Most Common: 
● Gastrointestinal adverse events including: 
○ Nausea 
○ Vomiting 


 
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○ Constipation 
○ Diarrhea 
○ Dry mouth 
○ Flatulence (gas) 
○ Dyspepsia (discomfort of the abdomen) 
○ Abdominal discomfort 
These occur most commonly during the first week of study treatment (21-32%)  
● Sexual dysfunction (14-34%)  
 
Less Common: (1-10%)  
● Dizziness  
● Dizziness  
● Somnolence (sleepiness)/sedation  
● Fatigue  
● Insomnia  
● Abnormal dreams  
● Hyperhidrosis (increase sweating)  
● Arthralgia (joint pain)  
● Decreased appetite  
● Itchy skin 
● Nasopharyngitis (common cold) 
 
 
 
  
 
Rare: (less than 1%)  
● Nervous system disorders  
● Skin and subcutaneous tissue disorders  
● Psychiatric disorders  
● Abnormal bleeding  
● Clinical worsening or suicide risk  
 
Serotonin Syndrome has been reported with serotonergic antidepressants (SSRIs [selective 
serotonin reuptake inhibitors], SNRIs [serotonin–norepinephrine reuptake inhibitor], and others), 
including with vortioxetine both when taken alone, but especially when co-administered with 
other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, 
tramadol, tryptophan, buspirone, and St. John's Wort). Increased levels of serotonin may cause 
signs and symptoms that can range from mild (shivering and diarrhea) to severe (muscle rigidity, 
fever and seizures). 
 
Treatment with serotonergic antidepressants (SSRIs, SNRIs, and others) may increase the risk of 
abnormal bleeding. There is an increased risk of bleeding when vortioxetine is co-administered 
with nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect 
coagulation.  
 
Activation of Mania/Hypomania can occur with antidepressant treatment.  


 
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Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated 
anatomically narrow angles treated with antidepressants.  
 
Hyponatremia (decreased levels of sodium in the blood) can occur in association with the 
syndrome of inappropriate antidiuretic hormone secretion (SIADH). This can cause:  
● Confusion 
● Seizures 
● Fatigue 
● Low levels of consciousness 
 
Post-Market Adverse Reactions 
The following adverse events have been identified during post-approval use of vortioxetine. 
These events are reported voluntarily from a population of uncertain size, and it is not possible to 
reliably estimate their frequency or establish a causal relationship to drug exposure. 
● Hyperprolactinaemia (high levels of prolactin [a hormone] in the blood) 
● Acute pancreatitis 
● Anaphylactic reaction 
● Serotonin syndrome, headache 
● Agitation, aggression 
● Angioedema 
● Hemorrhage (bleeding) (including contusion, ecchymosis [bruising], epistaxis 
[nosebleed], gastrointestinal or vaginal hemorrhage) 
 
As with taking any drug, there is a risk of allergic reaction.  If you have a very serious allergic 
reaction, you may be at risk of death.  Some symptoms of allergic reactions are: 
● Rash 
● Wheezing and difficulty breathing 
● Dizziness and fainting 
● Swelling around the mouth, throat or eyes 
● A fast pulse 
● Sweating 
 
Please seek treatment immediately and tell the study doctor and study staff if you have any of 
these symptoms.  
 
Risk of Blood Sampling:  
Blood samples will be drawn from a vein with a sterile needle, usually in the arm. The risks with 
drawing blood are pain, swelling, bruising, feeling faint, and rarely, infection at the site of the 
needle stick.  
 
Risks with fMRI 


 
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Magnetic Resonance Imaging (MRI) is a test that uses a magnetic field and pulses of radio wave 
energy to make pictures of organs and structures inside the body. There are few potential risks of 
having an MRI scan, as it is a non-invasive procedure and does not involve any radiation. The 
main potential risk comes from loose metal objects, which, if taken near the scanner, could be 
dangerous. The combination of the noise of the scanner and confined space can also be stressful 
for people who feel uncomfortable in closed spaces. Please see the section “fMRI Participation 
(Optional)” for more information.  
 
Risks with Email Communications 
BCDF will be using email communications to send you information about the study, schedule 
appointments, respond to any emails you send and provide any personal health information you 
may request (for example. copy of blood results). You will also be asked to send a copy of your 
COVID-19 positive test result (if you have one) via email - this document may contain some of 
your personal health information.  
 
To minimize risks associated with email communications, BCDF will be using encryption 
technology to send emails with personal health information. Encryption scrambles the contents 
of an email so that only those with access to a secret key or password can unscramble and read it. 
Encryption minimizes the risk of unauthorized collection, use or disclosure of information.  
 
However, please be aware that all electronic communication carries some risk. You may 
withdraw your consent to communicate with BCDF via email at any time. Please contact BCDF 
if you do not wish to use this method of communication.  
 
Other Risks 
Being in this study may make you feel uncomfortable. You will be asked personal questions 
about your medical history. You may refuse to answer questions or stop the interview at any time 
if there is any discomfort. Administering the cognitive testing may sometimes be frustrating 
particularly if you are not performing as well as you think you should, and may also lead to mild 
mental and physical fatigue.  
 
If you receive placebo (the inactive substance) as part of this study, your symptoms of post-
COVID-19 condition may not improve or may get worse. 
 
Voluntary Participation  
Your participation in this study is voluntary. You may decide not to be in this study, or to be in 
the study now and then change your mind later.  
 
You will be provided in a timely manner with new information that is learned during the study 
that might affect your decision to stay in the study.  
 
If you decide not to participate, or to withdraw from the study, your medical care or legal rights 
will not be affected.  


 
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The study doctor may also withdraw you from the study if your condition worsens, if you do not 
follow the study doctor’s instructions, if the study doctor feels it is in your best interests to be 
withdrawn, if the study sponsor discontinues the study, or for administrative reasons. You can be 
withdrawn without your consent, but the study doctor will tell you why.  
 
You may also withdraw from the study should you become pregnant, have an increase in risk of 
suicide ideation and any adverse events that, in the opinion of the study doctor, puts you at risk at 
any point during the study. 
 
You should discuss your birth control methods with the study doctor and ask for guidance about 
preventing pregnancy. 
 
Alternatives to Participation 
Currently, there are no approved alternative treatments for post-COVID-19 condition. This 
research study is for research purposes only. The only alternative is to not participate in this 
study.  
 
Please talk to the study doctor about your options before you decide whether or not you will take 
part in this study. 
 
Confidentiality  
Personal Health Information  
If you agree to join this study, the study doctor and his study team will collect your personal 
health information that they need for the study. Personal health information is any information 
that could be used to identify you and includes your:  
● Name  
● Address  
● Date of Birth  
● New or existing medical records, which includes types, dates and results of medical tests 
or procedures.  
 
The information that is collected for the study will be kept in a locked and secure area by the 
study doctor for 25 years. Electronically collected data will also be stored on a secured platform 
for 25 years. Only the study team or the people or groups listed below will be allowed to look at 
your records.  
 
The blood collected for exploratory biomarker testing will be kept in a locked and secure facility, 
as would all data related to this information, and will not be shared with any outside sponsor or 
external vendor. Your blood samples (labelled with your participant ID) will be stored for a 
maximum of 15 years from the time of collection. 
 


 
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The study team can tell you what information about you will be stored electronically and may be 
shared outside of the study team.  
 
The following people may look at the study records and at your personal health information to 
check that the information collected for the study is correct and to make sure the study followed 
proper laws and guidelines:  
● The study sponsor or its representatives/partner/collaboration companies.  
● Representatives of Advarra IRB - an independent ethics committee that reviewed the 
ethical aspects of this study to help protect the rights and welfare of study participants.  
● Representatives of Health Canada, or other regulatory bodies (groups of people who 
oversee research studies), outside of Canada, such as the United States Food and Drug 
Administration (FDA).  
 
All data that is transferred will be coded to prevent identification of individual participants. The 
Canadian Data Protection Law will be followed, as a minimum.  
 
Study Information That Does Not Identify You  
Some study information will be sent outside of the study team. Any information about you that is 
sent out will have a code and will not show your name or address, or any information that 
directly identifies you. The code, with which your data is identifiable, will be stored for a 
minimum of 25 years.  
 
The information may be shared with the Sponsor’s partner companies or with national and 
international regulatory agencies to help answer the study question, to develop future studies on 
this product or for research related to this study.  
 
All information collected during this study, including your personal health information, will be 
kept confidential and will not be shared with anyone outside the study unless required by law.  
 
You will not be named in any reports, publications, or presentations that may come from this 
study.  
If you decide to leave the study, the information about you that was collected before you left the 
study will still be used. No new information will be collected without your permission.  
 
By signing and dating this information and consent form, you consent to the collection, access, 
use and disclosure of your information as described above. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
Rights as a Participant  


 
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If you are harmed as a direct result of taking part in this study, all necessary medical treatment 
will be made available to you at no cost.  
 
By signing and dating this form, you do not give up any of your legal rights nor does this form 
relieve the study doctor or involved institution from their legal and professional responsibilities.  
 
Benefits of Participation  
No direct benefit is guaranteed to you from taking part in this study. Your condition may or may 
not improve, and could possibly even worsen. The results of this study may help the study team 
validate an antidepressant for cognitive function in individuals with post-COVID-19 condition. 
 
Costs and Compensation  
There is no cost to you, your private medical insurance (if any), or the public health insurance 
plan, for study procedures. The study drug will be provided at no cost for the duration of the 
study.  
 
In-Person Participant Compensation:  
You will be compensated up to $500 CAD if you complete the study. You may choose to receive 
your compensation in installments throughout the study (Week 2 - $125, Week 4 - $125, Week 8 
- $250) or receive one payment for the full amount at the end of your last visit (Week 8). If you 
participate in the optional fMRI scans and cognitive tasks, you will receive the amount of money 
you will receive during the cognitive task, in addition to $500.  The additional cognitive task 
may also be administered as a standalone assessment (outside of fMRI). Participants who 
complete it will be compensated with what they earn from this task in addition to the $500. This 
additional amount can vary from approximately $20-80.  
 
You may also receive an additional $50 for completion of exploratory blood work. 
 
Remote Participant Compensation: 
You will be compensated up to $250 CAD if you complete the study. You may choose to receive 
your compensation in installments throughout the study (Week 2 - $31.25, Week 4 - $31.25, 
Week 8 - $62.50) or receive one payment for the full amount at the end of your last visit (Week 
8). 
 


 
Brain and Cognition Discovery Foundation / Protocol Number BCDF002 
Page 18 of 20   
 
 
Roger McIntyre, MD, FRCPC 
NCT05047952 
1-Jun-2022 
 
Whom to Contact About This Study  
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the study doctor at the 
telephone number listed on the first page of this consent document. If you seek emergency care, 
or hospitalization is required, alert the treating physician that you are participating in this 
research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants. If you have any questions about your rights as a research 
participant, and/or concerns or complaints regarding this research study, contact: 
 
● By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
● or call toll free:    877-992-4724 
● or by email:          adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00055939. 
 
You will receive an electronically signed and dated copy of this consent form via email. If 
you wish to receive a printed copy of this consent form, please let us know. 


 
Brain and Cognition Discovery Foundation / Protocol Number BCDF002 
Page 19 of 20   
 
 
Roger McIntyre, MD, FRCPC 
NCT05047952 
1-Jun-2022 
 
Consent  
 
1. I confirm that the information regarding the study has been explained to me, that I have 
read and understood all pages of the participant information sheet, and that I have had the 
opportunity to ask questions regarding the study and these have been answered to my 
satisfaction.  
2. I understand the risks and the benefits that may result from taking part in the study.  
3. I understand that my participation is voluntary and that I am free to withdraw from the 
study at any time, without giving a reason, and without my medical care or legal rights 
being affected.  
4. I understand that I may withdraw my consent without giving a reason. The consequences 
of my withdrawal will be that no new information will be collected, but that already 
collected data will be used.  
5. I understand that I will be randomly assigned vortioxetine or placebo during the 8-week 
study period. 
6. I understand I will have to take one pill every day for 8 weeks.  
7. I am currently not pregnant and do not plan to become pregnant during the study. I 
understand it is my responsibility to use appropriate methods of contraception during the 
study.  
8. I am aware that the combination of vortioxetine and other antidepressants has not been 
well characterized for safety and efficacy and I understand that such a combination would 
be considered investigational.  
9. I accept that data collected for the study may be disclosed by Brain and Cognition 
Discovery Foundation to its partners as well as the authorities in and outside of the 
Canadian territory, including the European Union with the purpose of evaluating safety, 
efficacy, and cost/effectiveness of vortioxetine. I am aware that an identification number 
and my date of birth (month and year only) are linked to the data; however, other 
identifying information will not be transferred.  
10. I understand that the study doctor is not my most responsible physician (MRP) but will 
provide care and evaluation in the context of the study during the 8-week active study 
period and 2-week optional follow-up.  
11. I agree to email communications to/from BCDF, which may include personal health 
information. I understand that electronic communication carries some risk.  
12. I will not participate in other studies for the duration of this study. 
13. I agree to take part in the above study by signing and dating below.  
14. The study doctor has my permission to tell my regular doctor about my being in this 
study:  YES  or      NO  
15. I agree to participate in the optional fMRI scans:  
YES  or      NO  
16. I agree to participate in the optional exploratory blood analyses for future research (only 
for participants seen in-person) :  
YES  or      NO 
 
___________________________ 
 
__________________________ 
 


 
Brain and Cognition Discovery Foundation / Protocol Number BCDF002 
Page 20 of 20   
 
 
Roger McIntyre, MD, FRCPC 
NCT05047952 
1-Jun-2022 
 
Study Participant’s Name 
Study Participant’s Signature 
_______________
Date 
 
___________________________ 
Name of Person Obtaining Consent 
 
__________________________ 
Signature 
 
_______________ 
Date 
 
 
___________________________ 
Name of Study Doctor 
 
 
__________________________
Signature 
 
 
_______________
Date