Clinical trial NCT03272711
Conditions: Age-related Cognitive Decline
Keywords: Vortioxetine Elderly Online cognitive training
Sponsor: Washington University School of Medicine
Start date: 2016-08-31; Completion date: 2019-01-24
Enrollment: 129 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to examine the potential benefits of vortioxetine in combination with at-home computerized cognitive training program to improve cognition, such as memory, attention, and concentration. This study will compare the effectiveness of vortioxetine plus cognitive training versus placebo plus cognitive training.

Detailed description:
The purpose of this research study is to examine the potential benefits of vortioxetine in combination with at-home computerized cognitive training program to improve cognition, such as memory, attention, and concentration. This study will compare the effectiveness of vortioxetine plus cognitive training versus placebo plus cognitive training.

Vortioxetine is considered investigational when used as a treatment for age-related cognitive decline, which means that it has not been approved by the U.S. Food and Drug Administration for this purpose. Vortioxetine is approved by the U.S. Food and Drug Administration as a treatment for depression, and also goes by the name Trintellix (formerly known as Brintellix). That means that, while the drug itself is approved by the FDA, it is not approved for the reasons the investigators are using it in this study.

Participation in this study entails an estimated 6 study visits over the course of approximately six months. Participants will complete various assessments at our lab at the Washington University School of Medicine along with check-in visits in-person or over the phone. Additionally, they will participate in at home computerized cognitive training for approximately six months, supplemented with either vortioxetine or placebo.

The investigators will assess memory and problem-solving abilities using paper and pencil, computerized measures, and self-assessments of how participants feel. These tests could include numbers, letters, symbols, words, or sentences. These tests will be repeated throughout the study. If eligible to do so, participants will complete a baseline MRI scan.

A subset of participants who completed a baseline MRI scan will complete another MRI scan after approximately 26 weeks of vortioxetine or placebo and at home computerized cognitive training.

Arms: arm 1: Vortioxetine (10 mg) plus cognitive training 5 times weekly for 30 minutes a day arm 2: Placebo plus cognitive training 5 times weekly for 30 minutes a day
Interventions: intervention 1: Vortioxetine 10 mg intervention 2: Cognitive training program
Intervention descriptions: intervention 1: None intervention 2: Online training program, 30 minutes a day, 5 times a week

Protocol documents:
Prot_SAP_000.pdf: 
 
1 
 
 
Remediation of Age-related Cognitive Decline: Vortioxetine and 
Cognitive Training 
 
 
!NCT03272711 
 
 
 
 
September 23, 2016
Study Protocol & Statistical Analytic Plan 


 
2 
IISR GUIDE: STUDY INFORMATION 
Date:  (09/23/2016) 
Protocol Version: Sixth 
Country(s) the study will be conducted 
in:  
USA 
Compound/Product: (Generic Drug 
Name)  
Vortioxetine 
Study Type (ie, clinical, non-clinical):  
Clinical 
Study Title:  
“Remediation of age-related cognitive 
decline: vortioxetine and cognitive training” 
(IISR-2014-100821; PI: Eric Lenze, M.D.). 
 
Indication (List Area of Focus: 
Gastroenterology, Diabetes/Metabolism, 
Hypertension, Central Nervous System, 
Respiratory, Nephrology, Other):  
Age Related Cognitive Decline (Central 
Nervous System) 
 
INVESTIGATOR CONTACT INFORMATION 
Number of sites 
1 (Washington University) 
Principal Investigator Contact: 
 
Principal Investigator Name 
Eric Lenze, M.D. 
Organization Name 
Washington University School of Medicine 
Address 
660 S. Euclid, Campus Box 8134 
St. Louis, MO 63110 
Telephone 
314-362-5154 
Fax 
314-362-4260 
E-mail address 
lenzee@psychiatry.wustl.edu 
Co or Sub-Investigator(s) Contact (if 
applicable): 
 
Sub-Principal Investigator Name 
Christopher Bowie, Ph.D. 
Organization Name 
Queen’s University 
Address 
Toronto, Canada 
Telephone 
Fax 
E-mail address 
613-533-3347 
613-533-2499 
bowiec@queensu.ca 


 
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Study Assistant(s)/Coordinator(s) 
Contact: 
 
Name 
(address, phone number, email) 
Julie Schweiger 
660 S. Euclid, Campus Box 8134 
St. Louis, MO  63110 
314-362-3153 
schweigj@psychiatry.wustl.edu 
 
Institution’s Contracts or Grants office 
contact: 
 
Name 
(address, phone number, email) 
Tesha Myers 
660 S. Euclid, Campus Box 8134 
St. Louis, MO  63110 
314-362-2452 
myerst@psychiatry.wustl.edu 
Name and contact information of 
person completing this form: 
(name, address, phone number, email) 
Eric Lenze, MD 
660 S. Euclid, Campus Box 8134 
St. Louis, MO  63110 
314-362-5154 
lenzee@psychiatry.wustl.edu 
 
RESOURCES REQUESTED 
Resource Requested: 
(Drug, Funding, or Drug & Funding) 
Drug & Funding 
Estimated Study Budget: 
(Enter total here - including direct, indirect 
cost and institutional overhead); -  
$ 600,048.86 
Do you have additional funding sources 
for this project? 
(If Yes, please explain) 
No 
Dosage and Formulation: 
10mg 
 
Estimated Total Drug Supply for Study:  
(number of tablets, vials)  
18250 vortioxetine 10mg 
18250 matching placebo 


 
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Total # of Subjects:  
100 
 
Study Timeline 
Planned Activation Study: (Month/Year) 
Study activation is final regulatory authority 
approved protocol and fully executed 
contract  
 
April 29, 2016 
 
Study Activation to First Patient In: 
(Months) (n/a for non-clinical study) 
3 
 
First Patient In to Last Patient Out: 
(Months) (n/a for non-clinical study) 
18 
Monthly enrollment rate (days)(n/a for non-
clinical study): 
1 participant randomized per 2.5 working 
days (= 100 in one year) 
Treatment duration (in months) (n/a for 
non-clinical study): 
6 
Number of Study sites/depots (n/a for non-
clinical study) 
1 
Completion of Data Analysis: (# Months) 
2 
Completion of Final Study 
Report/Manuscript: (Month/Year) 
8/1/17 (or earlier): provide report of acute 
phase study outcomes to sponsor. 
2/1/18 (or earlier): provide report of one-
year study outcomes to sponsor. 
4/1/18 (or earlier): submit results to a peer-
reviewed journal. 
Publication Plan: (target journal, target 
conference) 
Potential journals include NEJM, Lancet, 
JAMA, and Journal of the American 
Geriatrics Society.  Above publication plan 
may be time-adjusted depending on date 
of funding; it assumes one year for 
recruitment, 6 weeks for acute phase, 
additional 22 weeks for long-term 
outcomes, and 8 weeks for data cleanup, 


 
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analysis, and writing up of results. 
 
STUDY PROPOSAL 
Study Rationale: 
Background: 
We propose to test vortioxetine, in combination with a cognitive training program, to remediate 
age-related cognitive decline, in a randomized clinical trial.  The vast majority of older adults will 
experience some deterioration in cognitive function as they age. This age-related cognitive 
decline varies widely between individuals, with individual differences related to preclinical 
Alzheimer’s pathology, cerebrovascular changes, mood/stress, and genetic and other 
differences.  Age-related cognitive decline can have substantial influence on quality of life, 
character of personal relationships, and the capacity for making informed decisions about 
health care, retirement, and other issues faced daily by millions of older adults. Cognitive 
training is beneficial for age-related cognitive decline; the Advanced Cognitive Training for 
Independent and Vital Elderly (ACTIVE) study, a large randomized trial of a cognitive 
intervention in an older population with normal cognitive ability, showed that targeted cognitive 
training has beneficial and long-lasting effects on specific functions (Ball et al, JAMA 2002).  
Rationale:  
The need for combining vortioxetine with a cognitive training program is to increase the effect 
size of the cognitive benefit.  Computerized cognitive training helps older adults to preserve and 
enhance their cognitive function – but with a small overall effect size (Lampit et al, PLOS 
Medicine 2014).  The rationale for a combined intervention is based on preclinical animal 
models suggesting that combined interventions (i.e., pharmacologic + behavioral interventions) 
may have greater pro-cognitive benefits through synergistic actions.  This assertion may be 
particularly relevant to vortioxetine, as its combination with cognitive training could robustly 
drive beneficial plasticity of the aging brain, resulting in significant improvement (or remediation) 
in memory and executive function of older adults with age-related cognitive decline.  At the 
same time, cognitive training programs are automated and therefore offer a feasible and 
scalable combination with pharmaceutical treatment.  
We propose doing so in a framework that allows for an understanding of contributors to age-
related cognitive decline and how they predict individual differences in vortioxetine treatment 


 
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response.  
The project will extend findings from the existing vortioxetine studies (particularly the geriatric 
depression study, the FOCUS and CONNECT studies, and preclinical work elucidating 
vortioxetine’s pro-cognitive mechanisms of action).  Specifically, data from this study will (1) inform 
projects currently under development, particularly in the area of mild cognitive impairment (MCI), 
and (2) clarify whether age-related cognitive decline is a potential target for a new indication.  
Along these lines, the FDA has indicated that approval for drugs for “pre-MCI” would be possible 
given a benefit for a cognitive outcome with an accelerated approval process, given the urgent 
need for disseminable treatments in the very early stages of cognitive decline (personal 
communication, George Nomikos; and Kozauer & Katz, NEJM 2013).  (3) Most importantly, the 
project would pave the way forward for treatment approaches for this extremely common age-
related syndrome that is expected to affect the majority of aging adults.   
Finally, the project is led by a PI who has repeatedly shown the ability to meet ambitious 
recruitment and completion timelines and succeed in demonstrating benefits of pharmacological 
treatments for symptoms and cognition in older adults, in both industry-sponsored and 
government-funded studies. 
Hypothesis:  
(1) Hypothesis 1: Vortioxetine will boost the acute and long-term cognitive benefits of 
computerized cognitive training in older adults with age-related cognitive decline who receive 
computerized cognitive training. 
H1a will test the hypothesis that participants randomized to vortioxetine will have a greater acute 
improvement in neuropsychological functioning than those randomized to placebo.  This will be 
tested using acute (week 0 and week 4) data. 
H1b will test whether participants randomized to vortioxetine will have a better long-term course in 
neuropsychological functioning than those randomized to placebo.  This will be tested using all 
longitudinal data (week 0, week 4, week 12, and week 26). 
Hypothesis 2: Vortioxetine will improve everyday functioning in older adults with age-related 
cognitive decline who receive computerized cognitive training. 
H2 will test whether participants randomized to vortioxetine will have a better long-term course in 


 
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function (using the UPSA) than those randomized to placebo.  This will be tested using all 
longitudinal UPSA data (week 0 and week 26). 
Primary Aim/Objective:  
Test the efficacy of vortioxetine for acutely improving neuropsychological functioning on the NIH 
Toolbox Cognitive Battery in 100 participants aged 65 and older with age-related cognitive 
decline, who will receive computerized cognitive training and will also be randomized 1:1 to 
vortioxetine or placebo.   
Secondary Aim/Objective: (if applicable) 
Test the long-term (26 week) efficacy of vortioxetine’s benefits.  
Test the functional benefits of vortioxetine. 
Explore brain-based predictors (moderators) of vortioxetine treatment efficacy. 
Primary Endpoints:  
Our primary outcome measures will be the total fluid cognitive score from the NIH Toolbox as well 
as the speed of cognitive improvement.  The NIH Toolbox will be carried out at baseline and after 
the lead-in phase (to establish a baseline and clarify inclusion into the study) and at 4, 12, and 26 
weeks post-randomization. 
Secondary Endpoints:  
As a secondary outcome, we will assess participant function using the UCSD Performance-Based 
Skills Assessment (UPSA), which has been shown to be sensitive to the cognitive effects of 
vortioxetine. 
Study Plan  
The key design features are: 
(1) Parallel-group randomized, double-blinded controlled trial of up to 10mg vortioxetine vs 
placebo, 50:50 randomization.   
(2) Randomize 100 adults aged 65+ with age-related cognitive decline.  A sample size of 100 
balances power and feasibility concerns, allowing for a reasonably-powered preliminary 
examination of efficacy and exploration of individual differences while providing a finding within a 
near-term time frame (initial results at the end of one year of funding). This will require recruiting 
and consenting, in our estimate, approximately 120 individuals, with approximately 10% being 


 
Page 8 of 21 
removed in the baseline and after lead-in phases. 
(3) All participants receive cognitive training using a well-validated program, “Scientific Brain 
Training Pro” (www.scientificbraintrainingpro.com).  Prior to randomization, all participants receive 
a training session with research staff and then an “open label lead-in” of two weeks of cognitive 
training (with their home computer), 5 times weekly for 30 minutes/day.   
Study design and schedule of procedures: 
 
Description of the cognitive training program: Cognitive training techniques result in 
physiological adaptation of the brain as a result of neuroplasticity, leading to tissue growth and 
more efficient neurophysiological processing.  These techniques increasingly rely on drill and 
practice computerized exercises, which include graded changes in difficulty level to adapt to the 
dynamic performance of the individual. That is, the participant’s performance guides the task 
parameters and a trial-by-trial change in difficulty level is made to keep the activity challenging 
enough to stimulate neuroplasticity, but not so difficult that repeated failure produces 
discouragement and withdrawal. The training is feasible with older and even novice computer 
Screen (week -3) assessment: 
SCID/DSM-IV 
Baseline (week -2) assessment: 
Neuropsychological functioning 
(NIH Toolbox) 
MRI (if eligible) 
• Age 65+ 
• Age-related cognitive decline 
• No current depression, dementia, or MCI 
N=50 
4 weeks vortioxetine, up to 
10mg daily plus cognitive 
training, 5x weekly 
Randomization (week 0) 
assessment: 
Neuropsychological 
functioning (NIH Toolbox) 
UPSA 
ALL receive 2 weeks cognitive training, 5x weekly.  
After two weeks: remove from study (and do not randomize) 
all who have poor adherence or do not meet study criteria. 
N=50 
4 weeks placebo, plus cognitive 
training, 5x weekly 
N=50 
22 weeks vortioxetine, up to 
10mg daily plus cognitive 
training
N=50 
22 weeks placebo, plus 
cognitive training 
acute 
long-term 
Outcome assessments 
(weeks 4, 12, and 26): 
Neuropsychological 
functioning (NIH Toolbox) 
UPSA (week 26) 
 


 
Page 9 of 21 
users; the participant logs into the activity online through a simple interface that only displays a 
request for username and password and the exercises appear automatically through a pre-
selected order. Thus, participants click “play” or “exit”, reducing the visual distractions and 
complexity that might be associated with computer use in general.  There are 28 different cognitive 
exercises, each with 30 levels of difficulty. Training progresses from basic (i.e., processing speed, 
attention) to more complex (i.e., working memory, executive functions) cognitive functions. 
Difficulty levels change adaptively by increasing following consecutive trials of 80% success or 
better and decreasing following consecutive trials of 70% success or less. Feedback is provided 
after each trial and participants have access to visual displays of their progress on each task 
throughout their training period. A one-hour orientation and training session is completed with 
participants following baseline assessment. This includes psychoeducation to the purpose of 
improving cognition, which is integrated into the participant’s own profile of cognitive strengths and 
limitations and their self-defined goals for functioning. A manual is provided to participants with 
clear instructions, goals, and strategies for each of the exercises. The program has a moderated 
forum wherein participants share their cognitive strategies and how the tasks are relevant for 
everyday life skills. 
Rationale for all participants to receive cognitive training: numerous studies already have 
demonstrated the cognitive benefits of cognitive training for older adults with age-related cognitive 
decline.  This study would be the first to examine vortioxetine’s benefits when taken together with 
cognitive training.  Combining medication with cognitive training is expected to synergize with the 
drug's putative pro-cognitive mechanisms of action; this should demonstrate greater cognitive 
benefits than has been shown in most of the existing studies with drug alone.  Another advantage 
of this approach is that the project may be more appealing for individuals seeking help for their 
cognition.   
Rationale for a lead-in phase: The lead-in phase (cognitive training only; no medication) allows for 
a confirmation of participants’ motivation and willingness/ability to carry out the cognitive training.  
For those unable or unwilling to do so, they can then be removed from the study at the end of the 
two-week lead-in phase, without penalizing the randomized controlled trial.  Additionally, 
sequencing the treatments (providing cognitive training first and then medication later) is less 
taxing for participants than introducing two treatments simultaneously.  Finally, those who hit a 
ceiling effect on neuropsychological testing after two weeks of training will be removed prior to 


 
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randomization.  These advantages improve our ability to discern specific efficacy of vortioxetine. 
 (4) At Baseline visit (baseline visit = prior to first dose of vortioxetine or placebo), all eligible 
participants will receive a structural and resting-state functional connectivity brain MRI.  This will 
examine brain markers of age-related cognitive decline that could be treatment response 
predictors.  Doing so would clarify inclusion/exclusion criteria for future cognitive aging research 
with vortioxetine. 
(5) The RCT has two phases, acute and long-term.  The acute phase is four weeks long, during 
which participants receive either up to 10mg vortioxetine or placebo, and all participants also 
receive four weeks of cognitive training at home, 5 times weekly for 30 minutes/day, which our 
team has previously found to be an acceptable amount, even in very ill samples.  The long-term 
phase would last an additional 22 weeks, during which participants remain (double-blinded) on 
their vortioxetine vs placebo assignment.  During that time, participants will also continue to 
receive cognitive training (with their home computer), 5 times weekly for 30 minutes/day. 
Schedule of assessments: 
 
 
Week of study 
-3 
-2 
0* 
4 
12 
26 
Outcome measures 
 
 
(Hypothesis 1) Cognitive battery 
 
X 
X 
X 
X 
X 
(Hypothesis 2) UCSD Performance-Based Skills 
Assessment (UPSA) 
 
 
X 
 
 
X 
 Baseline assessments 
 
 
Structured Clinical Interview for DSM-IV 
Disorders (to exclude major depression and 
other disorders) 
X 
 
 
 
 
 
MRI (structural + resting state fMRI) 
 
X 
 
 
 
 
* Note: week 0 = randomization visit. 
Rationale for study length: the four-week acute phase allows for a rapid test of vortioxetine’s 
benefits in the setting of co-administered cognitive training.  Four weeks was chosen because it is 


 
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a sufficient length to achieve steady state concentrations of vortioxetine, and to expect 
neuroplasticity (and thus neuroplasticity enhancing) effects of the drug in combination with 
training.     
The long-term phase duration (26 weeks) is chosen for several reasons.  First, research with other 
neuroplasticity-enhancing intervention (namely, aerobic exercise) has suggested that longer 
duration of intervention may be necessary to see the full cognitive benefits.  Therefore, it is 
possible that significant effects of vortioxetine in this context would not be apparent until 26 weeks.  
Second, this would provide valuable data on the long-term cognitive impact of vortioxetine, and the 
functional benefits that result.   
With respect to adherence to 26 weeks of cognitive training, in our recent studies, we had success 
with this training period (5 to 7x per week) over a 12 week period with no evidence for substantial 
drop off during that period. (Bowie et al, J Nerv Mental Disease, 2013).  Compliance over six 
months may be lower, but this is not expected to change study results and will be informative for 
future efforts to tie vortioxetine to cognitive-enhancing behavioral interventions. 
Adherence monitoring to the cognitive training program and the study medication: the cognitive 
training program has built-in adherence monitoring.  During the pre-randomization lead-in phase, 
we will use these data to determine whether or not to include participants in the RCT.  During the 
RCT, we will use adherence monitoring to provide motivational feedback to participants to 
reinforce or increase adherence.  We will examine medication adherence via self-report and pill 
count, which in our prior studies has provided >99% accurate data compared to a gold standard of 
blood tests of medication concentration. 
Blinding measures taken to minimize bias: Subjects receive blinded study medication.  
Investigators will also be blinded; only the data manager will know treatment assignment.  It is our 
goal to get key results to Takeda/Lundbeck as rapidly as possible.  We will prepare an interim data 
analysis and a study report for Takeda/Lundbeck once the last participant has completed the 
acute phase, while keeping the rest of the team blinded.  This would be the only such interim 
analysis.  Prior to completing any final analyses for publication in a peer-reviewed journal, we will 
close the dataset and remove the blind. 
 


 
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Inclusion criteria: (1) Community-living men and women age 65 and older; (2) Age-related 
cognitive decline as defined by (a) self-reported cognitive dysfunction that is attributed to the aging 
process (in response to screening questions to the participant); (b) ability to complete cognitive 
battery, but still scoring less than 1 standard deviation above age-matched norms at both baseline 
and after the two-week cognitive training lead-in.  Both a lower limit (to exclude dementia and mild 
cognitive impairment) and upper limit (to avoid ceiling effects) are needed.  An upper limit of >1 
standard deviation above age-matched norms reflects that with typical aging, older adults have 
declines in the domains of memory, executive functioning, and information processing speed 
compared to younger cohorts (thus have age-related cognitive decline).  
Rationale for these age-related cognitive decline criteria: There is no clear consensus for how to 
define age-related cognitive decline for a clinical trial.  Based on consensus definitions of age-
related cognitive decline, and clinical trials by our group as well as other studies of vortioxetine, we 
propose three components: (1) the participant should endorse subjective difficulties with memory 
and/or concentration that are attributable to the aging process (rather than a lifelong problem such 
as ADHD); (2) At baseline, the participant should score below 1 standard deviation above the 
mean score of their age group in the NIH Toolbox total fluid cognition score, but still be able to 
complete the cognitive battery (as this inability to do so would indicate mild cognitive impairment); 
(3) After the initial two-week lead-in of cognitive training, the participant should continue to score 
below 1 standard deviation above the mean of their age group (to exclude individuals who 
“respond” to either simply repeating the neuropsychological testing or to brief cognitive training).  
These components should maximize our ability to detect a signal with vortioxetine in the RCT. 
Exclusion criteria: (1) Known dementia or other clinical neurodegenerative illness (e.g., 
Parkinson’s disease, cerebrovascular disease) per self-report, informant report, medical records, 
or neuropsychological testing. (2) Any current psychiatric disorder. (3) Medical conditions that 
suggest shortened lifespan, such as metastatic cancer; or would prohibit safe participation in the 
interventions, including cardiovascular disease or musculoskeletal conditions; or with the 
assessments. (4) Sensory impairment that would prevent participation. (5) IQ < 70 as estimated by 
the Wechsler Test of Adult Reading. (6) Alcohol or substance abuse within 6 months. (7) 
Concurrent cognitive training, such as brain-training software, or other interventions expected to 
affect neuroplasticity. (8) Psychotropic medications or those with likely CNS effects (none within 4 


 
Page 13 of 21 
weeks prior to study entry). 
Rationale for exclusion of patients with depression: There are methodological and safety reasons 
for this exclusion.  As previous studies of vortioxetine in older and younger adults with MDD have 
shown a cognitive benefit, we believe the next step is to examine cognitive benefits in a non-
depressed sample, to further demonstrate independence of cognitive benefits from vortioxetine’s 
antidepressant benefit.  Additionally, a non-psychiatrically ill population can remain safely off of 
antidepressants and other psychotropics for the duration of the RCT. 
Clarification of medical and medication exclusions: We will exclude the following medical 
conditions: 
any 
acute 
condition 
(e.g., 
active 
infection), 
uncontrolled 
condition 
(e.g., 
ongoing/unstable angina, poorly controlled diabetes or hypertension), progressive condition (e.g., 
stage 3 or 4 heart failure, or any neurodegenerative condition such as Parkinson’s), life-
threatening or life-shortening conditions (e.g., metastatic cancer), or any that is expected to affect 
cognitive function (e.g., hyper- or hypo-thyroidism) or ability to participate in the study (e.g., severe 
arthritis such that the participant could not carry out the neuropsychological tests).   
We will exclude all medications that have known or likely CNS effects.  These include not only all 
medications approved for psychotropic indications (e.g., antidepressants, antipsychotics, 
benzodiazepines, mood stabilizers), but also centrally-acting anticholinergics (e.g., oxybutynin), 
antihistaminergics (e.g., diphenhydramine), opioids (e.g., methadone) dopaminergic agents (e.g., 
ropinirole), and other medications with neuropsychiatric side effects (e.g., interferon), unless the 
use of the medication is rare and it can be avoided for at least 24 hours prior to cognitive tests. 
Safety Reporting (please do not change the safety section of the template) 
Institution/Investigator is solely responsible for reporting all Adverse Events and Serious Adverse 
Events to regulatory authorities, investigators, IRBs or IECs and Takeda, as applicable, in 
accordance with national regulations in the countries where the study is conducted.  
Regardless of expectedness or causality, all SAEs must also be reported in English to Takeda 
Pharmacovigilance or designee: 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s observation 
or awareness of the event 
All other serious (non-fatal/non life threatening) events within 4 calendar days of the 
sponsor-investigator’s observation or awareness of the event 
 
Takeda requires that all information be communicated to Takeda’s Pharmacovigilance 
Department as outlined in the study contract. 


 
Page 14 of 21 
 
All reported adverse drug reactions and safety issues related to Takeda compound must be 
included in the final study report. 
Describe procedures for reporting Adverse Events and Serious Adverse Events. 
Definitions:  
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered 
a medicinal product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product.  
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.   
 
An adverse drug reaction (ADR) is a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. This includes adverse reactions 
which arise from: use of a medicinal product within the terms of the marketing authorization; use 
outside the terms of the marketing authorization, including overdose, misuse, abuse and 
medication errors; and occupational exposure*. 
* This corresponds to the exposure to a medicinal product for human use as a result of one’s 
occupation, such as nurses who may handle products routinely in their occupational setting. 
 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the time of 
the event.  It does not refer to an event which hypothetically might have caused death if it 
were more severe). 
• Requires inpatient hospitalization or prolongation of an existing hospitalization . 
• Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require medical 
or surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent.   Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse; any organism, virus, or infectious 
particle (e.g., prion protein transmitting Transmissible Spongiform Encephalopathy), 


 
Page 15 of 21 
pathogenic or nonpathogenic, is considered an infectious agent.   
 
An IMPORTANT MEDICAL EVENT also includes any event described in Takeda Medically 
Significant AE List below: 
Acute respiratory failure/acute 
respiratory distress syndrome 
Anaphylactic shock 
Torsade de pointes/ventricular 
fibrillation/ventricular tachycardia 
Acute renal failure 
Malignant hypertension 
Pulmonary hypertension 
Convulsive seizures 
Pulmonary fibrosis 
Agranulocytosis 
Confirmed or suspected endotoxin 
shock 
Aplastic anemia 
Confirmed or suspected transmission 
of infectious agent by a medicinal 
product 
Toxic epidermal 
necrolysis/Stevens-Johnson 
syndrome 
Neuroleptic malignant 
syndrome/malignant hyperthermia 
Hepatic necrosis 
Spontaneous abortion/stillbirth and 
fetal death 
Acute liver failure 
  
 
Clarification should be made between a serious AE (SAE) and an AE that is considered severe in 
intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous.  The 
general term severe is often used to describe the intensity (severity) of a specific event; the event 
itself, however, may be of relatively minor medical significance (such as a Grade 3 headache).  
This is NOT the same as serious, which is based on patient/event outcome or action criteria 
described above, and is usually associated with events that pose a threat to a patient’s life or 
ability to function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious.  For example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 
3 (severe) but may not be considered serious.  Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations. 
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and permanently discontinue study drug.  The 
sponsor-investigator must fax a completed Pregnancy Form to the Takeda Pharmacovigilance or 
designee immediately.  The pregnancy must be followed for the final pregnancy outcome (i.e., 
delivery, still birth, miscarriage) and Takeda Pharmacovigilance or designee will request this 
information from the sponsor-investigator. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor-investigator must also immediately fax a completed Pregnancy Form to the 
Takeda Pharmacovigilance or designee. Every effort should be made to follow the pregnancy for 
the final pregnancy outcome. 


 
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Product Complaints and Medication Errors  
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals who 
identify a potential product complaint situation should immediately contact Takeda and report the 
event.   
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm.  While overdoses and underdoses 
constitute medication errors, doses missed inadvertently by a patient do not.  Individuals who 
identify a potential medication error situation should immediately contact Takeda (see below) and 
report the event. 
 
Phone: 1-877-TAKEDA7 (1-877-825-3327) 
E-mail: medicalinformation@tpna.com 
FAX: 1-800-247-8860 
Product complaints and medication errors in and of themselves are not AEs.  If a product 
complaint or medication error results in an SAE, an SAE form should be completed and sent to 
Takeda Pharmacovigilance. 
We will assess all participants prior to randomization with medical history and physical 
examination and routine safety laboratories (electrolytes, liver/kidney function, thyrotropin).  We do 
not anticipate routine assessment during the RCT with safety laboratories or physicals, as 
vortioxetine is an FDA-approved medication at this dose and such routine monitoring is not 
recommended with its clinical use.  We will assess and record vital signs at all in-person visits and, 
post-randomization, will assess for study medication side effects at all visits.  We will assess for 
and record adverse events (serious and nonserious) throughout the RCT. 
Statistical Analysis 
 
The PI and his research team will carry out all data analyses (although the data will be available to 
the sponsor) and publish findings from the study.  Efficacy analyses will be: primary – 
neurocognitive changes; secondary – functional changes. 
The rationale for the study design and its sample size of 100 is based on achieving the greatest 
possible statistical power within the feasibility confines of a single-site study.  Based on this 
sample size, we would have 80% power (at 2-tailed p<0.05) to detect a moderate effect size 
(d=0.55) for greater cognitive improvement in the vortioxetine group compared to the placebo 


 
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group. 
We will use the intention-to-treat principle in examining vortioxetine’s efficacy.  All data from all 
randomized participants will be included.  Given the common occurrence of non-treatment related 
dropout/nonadherence in this age group, we reduce the likelihood of these methodological 
problems by our screening/exclusion procedures, the lead-in phase, and the relatively short (4 
week) acute RCT phase. 
Our primary analytic strategy will be mixed effects models, where the treatment group by time 
interaction (from baseline to post treatment) will be the key analysis.  This is the preferred strategy 
to a remission analysis as it provides greater statistical power than a categorical endpoint.  Mixed 
effect models are also optimal for the intent-to-treat principle, as missing data are taken into 
account by the models. 
H1a will test the hypothesis that participants randomized to vortioxetine will have a greater acute 
improvement in neuropsychological functioning than those randomized to placebo.  This will be 
tested using acute (week 0 and week 4) data. 
H1b will test whether participants randomized to vortioxetine will have a better long-term course in 
neuropsychological functioning than those randomized to placebo.  This will be tested using all 
longitudinal data (week 0, week 4, week 12, and week 26). 
H2 will test whether participants randomized to vortioxetine will have a better long-term course in 
function (using the UPSA) than those randomized to placebo.  This will be tested using all 
longitudinal UPSA data (week 0 and week 26). 
We will also explore predictors of cognitive improvement using brain MRI data.  While this will be a 
more exploratory set of analyses, depending on results from H1a and H1b, we will examine 
whether MRI-derived data on (a) volumetric (b) white matter hyperintensities (c) connectivity within 
and between relevant cognitive circuits predicts both acute and long-term course of cognitive 
change in the vortioxetine vs. placebo groups. 
Data Management Plan 
The PI, Study Coordinator and/or other designated research staff will be responsible for data 
collection, error resolution, data entry and protecting the integrity of the data.   
Source Data: Source data includes information in original records or copies of clinical findings, 


 
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observations, ratings, or other activities in a study necessary for the reconstruction and evaluation 
of the study. 
Procedures: Source data received by the delegated individual responsible for data management 
should be reviewed for any missing data, incomplete fields or data outside the normal ranges in a 
timely manner.   If any discrepancies are raised at this point, these must be clarified and any 
queries recorded immediately. Any amendments made on the original data collection sheet will be 
documented, initialed and dated by the individual/s using a single line through method so as not to 
obscure the original data collected.  No correction fluid should be used.   
On completion of the above process, a delegated member of the research team will enter the data 
into REDCap (Research Electronic Data Capture data capture software developed by Vanderbilt 
University for clinical researchers). This web-based software allows researchers the ability to 
perform checks on the data during the entry process, as well as while the data is in the system. 
Additional benefits of REDCap are: Support of Multiple Data Types, Textbox Data Validation, Audit 
Trails / Data Logging, Data Quality Module, Double Data-Entry, Branching Logic to conditionally 
show/hide fields, Custom Reports, and Study Calendar tool. 
REDCap includes data import and export tools.  Exported data can be done so with the removal of 
identifying information, and to any of the following software packages:  CSV/Microsoft Excel, 
SPSS, SAS, R, Stata.   
Data collection safety and confidentiality: Procedures designed to maintain data confidentiality 
include (1) formal training sessions for all research staff emphasizing the importance of 
confidentiality, (2) specific procedures developed to protect participants’ confidentiality, and (3) 
formal mechanisms limiting access to information that can link data to individual participants. 
Electronic records (computer files, electronic databases, etc.): All electronic records will be 
collected and maintained in compliance with Washington University approved policy and practice. 
The risks of breaching confidentiality will be strictly limited by the use of locked and restricted 
access to data, as well as the use of participant ID numbers rather than names in the data 
base.  All sensitive electronic information is kept in password-protected files on a password-
protected computer. All other data will be entered and secured in a WUSM database system. 
Paper/hard copy records (hard copy surveys, questionnaires, case report forms, pictures, etc.): 
The risks of breaching confidentiality will be strictly limited by the use of locked and restricted 


 
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access to data, as well as the use of participant ID numbers rather than names in the data base. 
Medical records containing PHI and research records are kept in a locked cabinet behind two 
locks. All research records are kept and transported in closed containers (e.g., sealed envelope, 
closed bag, closed wheeled cart, etc.), all in compliance with Washington University approved 
policy and practice. No identifiers are included in any reports generated by this study. 
 
 


 
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Publication Plan (i.e., abstract, presentation, journal, conference, etc.) 
Our plans are as follows. 
8/1/17 (or earlier): provide report of acute phase study outcomes to sponsor. 
2/1/18 (or earlier): provide report of one-year study outcomes to sponsor. 
4/1/18 (or earlier): submit results to a peer-reviewed journal and for presentation at conferences. 
Potential journals include NEJM, Lancet, JAMA, and Journal of the American Geriatrics Society.  
Potential national conferences include the Gerontological Society of America and the American 
Association for Geriatric Psychiatry.  The above publication plan may be time-adjusted depending 
on date of funding; it assumes one year for recruitment, 6 weeks for acute phase, additional 22 
weeks for long-term outcomes, and 8 weeks for data cleanup, analysis, and writing up of results. 
Ethical and Regulatory Considerations 
Prior to initiating the study, the Principal Investigator will obtain written approval to conduct the 
study from the Washington University Institutional Review Board and send a copy to Takeda 
(gma.externalresearch@takeda.com). Should changes to the study become necessary, copies of 
written approvals from appropriate institutional ethical and/or regulatory committees will be sent to 
Takeda (gma.externalresearch@takeda.com). 
The Principal Investigator will register the study with clinical trials.gov prior to randomizing 
subjects. 
If an IND is required, the Principal Investigator will work with the FDA to obtain or prove 
exemption. 
References 
Ball K, Barch DB, Helmers KF, Jobe JB, Leveck MD, Marsiske M, Morris JN, Rebok GW, Smith 
DM, Tennstedt SL, Unverzagt FW, Willis SL; Advanced Cognitive Training for Independent and 
Vital Elderly Study Group.  Effects of cognitive training interventions with older adults: a 
randomized controlled trial. JAMA. 2002 Nov 13;288(18):2271-81. 
 
Bowie CR, Gupta M, Holshausen K, Jokic R, Best M, Milev R (2013): Cognitive remediation for 
treatment-resistant depression: effects on cognition and functioning and the role of online 
homework. J Nerv Ment Dis.  201(8):680-5. 
Kozauer N, Katz R. Regulatory innovation and drug development for early-stage Alzheimer's 
disease. N Engl J Med. 2013 Mar 28;368(13):1169-71. 
 
Lampit A, Hallock H, Valenzuela M. Computerized cognitive training in cognitively healthy older 
adults: a systematic review and meta-analysis of effect modifiers. PLoS Med. 2014 Nov 


 
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18;11(11):e1001756 
 
Supporting documentation/tables and graphs 
 
Tables/figures are embedded within the protocol. 
Attach a detailed Budget for all study related costs.  
 
Budget is provided (separate document)