Efficacy of Lu AA21004 on Cognitive Dysfunction in Major Depressive Disorder

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01564862
• Collaborator: (none)
• Enrollment: 602
• Locations: 92
• Arms: 3
• Duration (Months): 22
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effects of Lu AA21004, once daily (QD), on cognitive dysfunction in patients with major depressive disorder.

Condition or Disease	Intervention/Treatment	Phase
Depressive Disorder, Major	Drug: vortioxetine (Lu AA21004); Drug: Duloxetine; Drug: Placebo	Phase 2

Detailed Description

Lu AA21004 is under codevelopment by Takeda Global Research & Development Center, Inc. and H. Lundbeck A/S for the treatment of MDD.

This study will consist of a screening period within 10 days of the Baseline Visit followed by an 8-week double-blind treatment period and a one-week taper down period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 602 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Active-Referenced, Flexible Dose Study on the Efficacy of Lu AA21004 on Cognitive Dysfunction in Adult Subjects With Major Depressive Disorder (MDD)
• Study Start Date: Apr 1, 2012
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: Feb 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vortioxetine (Lu AA21004) QD Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Drug: vortioxetine (Lu AA21004); Lu AA21004 capsules
Active Comparator: Duloxetine QD Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Drug: Duloxetine; Duloxetine capsules; Other Names: Cymbalta
Placebo Comparator: Placebo QD Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).	Drug: Placebo; Placebo matching capsules

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 8 in the Digit Symbol Substitution Test (DSST) [Baseline and Week 8]

   The DSST assesses relative contributions of speed, memory, executive function and visual scanning. Participants are required to copy symbols that are paired with simple geometric shapes or numbers within a specific time for a total possible score of 0 to 133. Higher scores-correct number of symbols reflects greater objective cognitive functioning. An increase in score represents an improvement in an integrated measure of cognitive function. An Analysis of Covariance (ANCOVA) model was used with treatment and center as fixed factors and the Baseline value as a covariate.

Secondary Outcome Measures

1. Change From Baseline to Week 8 in the Perceived Deficits Questionnaire (PDQ) Attention/Concentration and Planning/Organization Subscore [Baseline and Week 8]

   PDQ is a patient-rated scale designed to subjectively assess cognitive dysfunction, comprising four 5-item subscales: Attention/Concentration, Retrospective Memory, Prospective Memory, and Planning/Organization for a total possible score of 0 to 40. The subscale Attention/Concentration is the sum of items 1, 5, 9, 13, and 17 with a range of 0-20; while the subscale Planning/Organization is the sum of items 4, 8, 12, 16, and 20 with the score range of 0 to 20. The scores of the subscales Attention/Concentration and Planning/Organization were summed. Higher scores reflect greater participant-perceived cognitive dysfunction in the domains identified. A decrease in score represents an improvement in subjective cognitive function in the domains identified. A Mixed Model Repeated Measures (MMRM) model was used with baseline*week, center, week, treatment and week*treatment as factors in the analysis.

2. Clinical Global Impressions-Improvement (CGI-I) Score at Week 8 [Baseline, Week 8]

   The CGI-I assesses the clinician's impression of the subject's state of mental illness improvement and consists of one question for the investigator: "Compared to his condition at the start of the study, how much has this patient changed?" which is rated on a seven-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change relative to baseline; 5=minimally worse; 6= much worse; 7=very much worse). Higher scores indicate greater worsening of illness. Values closest to 1 for this outcome measure indicate the greatest improvement of symptoms. A MMRM model was used with baseline*week, center, week, treatment and week*treatment as factors in the analysis.

3. Change From Baseline to Week 8 in the Trail Making Test (TMT-A) [Baseline and Week 8]

   The TMT is a two-part cognitive test. TMT-A assesses cognitive processing speed and consists of 25 circles distributed over a sheet of paper. Participants have 4 minutes to connect the circles as quickly as possible, without lifting the pen or pencil from the paper. Tester informs participant immediately whenever they make an error and allows for corrections by participants. Lower scores represent better speed of processing. A decrease in score over the study represents an improvement in speed in processing. An ANCOVA model was used with treatment and center as fixed factors and the baseline value as a covariate.

4. Change From Baseline to Week 8 in the Trail Making Test B (TMT-B) [Baseline and Week 8]

   The TMT is a two-part cognitive test. TMT-B assesses executive functioning and consists of 25 circles distributed over a sheet of paper. Participants have 4 minutes to connect the circles as quickly as possible, without lifting the pen or pencil from the paper. Tester informs participant immediately whenever they make an error and allows for corrections by participants. Lower score for TMT-B represents better executive function. A decrease in score over the study represents an improvement in executive function. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.

5. Change in Time From Baseline to Week 8 in the Stroop Test [Baseline and Week 8]

   The STROOP test assesses the ability to inhibit a prepotent response to reading words while performing a task that requires attention control. It comprises of 2 sheets with 50 words each, up to 50 correct responses for each of the congruent and incongruent Stroop tests. Participants have 4 minutes to name the ink color of each word. Lower time to complete the test indicates better performance. Higher number of correct responses indicates better responses. A decrease in the time to complete the tests and an increase in the number of correct responses both indicate improvement over the course of the study. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.

6. Change From Baseline to Week 8 in the Groton Maze Learning Test (GMLT) [Baseline and Week 8]

   The GMLT measures executive functioning and spatial problem solving. Participants learn a hidden pathway through a maze of 10 x 10 grid of tiles on a computer touch screen using step-by-step guess, with trial and error feedback after each step. Once the pathway is learned, participants repeat the same pathway four more times. It usually takes 5-6 minutes to administer this test. Lower score equals better performance. A decrease in score over the course of the study indicates improved executive function. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.

7. Change From Baseline to Week 8 in the Detection Task (DT) [Baseline and Week 8]

   The DT is a computerized test that measures simple reaction time and psychomotor speed. The task requires participants to respond by pressing a "yes" button as soon as an onscreen playing card is turned over and is red, and by pressing a "no" button if the card is not red. It takes 2 minutes to be administered. There is no minimum or maximum scores since it is a time-based assessment. Lower score equals better performance. A decrease in score over the course of the study indicates improved speed of processing and psychomotor function. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.

8. Change From Baseline to Week 8 in the Identification Task (IT) [Baseline and Week 8]

   The IT measured choice reaction time: the participant pressed a "yes" button whenever an onscreen playing card turned face up and was red, or a "no" button if the card was not red. The IT took on average 2 minutes to complete. Lower scores equal better performance. A decrease in score over the course of the study indicates improved visual attention/vigilance. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.

9. Change From Baseline to Week 8 in the One-Back Task [Baseline and Week 8]

   The One-Back test measures the cognitive domain of attention and working memory through yes or no responses to 30 trials. The task requires participants to report when a stimulus item presented serially is the same as an item one step back from the item at hand for a total correct responses 0 to 100. It usually takes 2-3 minutes to be administered. Higher scores equal better performance. An increase in score over the course of the study indicates improved attention/working memory. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.

10. Proportion of Cognitive Dysfunction Improvement Due to Improvement of Depression [Baseline and Week 8]

    Improvement of Cognitive Dysfunction is determined using the change from Baseline to Week 8 in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score and the Digital Symbol Substitution Test (DSST) total number of correct symbols. The MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression). The DSST assesses relative contributions of speed, memory, executive function and visual scanning. The proportion of direct effect from treatment = DSST difference / (DSST difference + coefficient*MADRS difference).

11. Change From Baseline to Week 8 in the MADRS Total Score [Baseline, Week 1, Week 4 and Week 8]

    MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. A negative change from Baseline indicates improvement.

12. Percentage of Participants With MADRS Response at Week 8 [Baseline and Week 8]

    MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. MADRS Response was defined as a ≥50% decrease in MADRS Total Score from Baseline.

13. Percentage of Participants in MADRS Remission at Week 8 [Week 8]

    MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. MADRS Remission was defined as a MADRS total score ≤10.

14. Change From Baseline to Week 8 in the Clinical Global Impressions-Severity (CGI-S) Score [Baseline, Week 1, Week 4 and Week 8]

    The CGI-S assesses the clinician's impression of the subject's current state of mental illness and consists of one question for the investigator: "Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?" which is rated on a seven-point scale (1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill). A MMRM model with baseline*week, center, week, treatment and week*treatment as factors was used for analyses.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.

2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.

3. The participant has recurrent MDD as the primary diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria (classification code 296.3x). The current MDE should be confirmed using the Mini International Neuropsychiatric Interview (MINI) V6.0.0.

4. The participant has received prescribed treatment for a previous episode of depression.

5. The participant has a MADRS total score ≥26 at both the screening and baseline visits.

6. Participant reports subjective cognitive dysfunction (such as difficulty concentrating, slow thinking, and difficulty in learning new things or remembering things).

7. The reported duration of the current major depressive episode (MDE) is at least 3 months

8. The participant is a man or woman between 18 and 65 years old, inclusive.

9. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from signing of the informed consent throughout the duration of the study and for 30 days after completion of the study.

Exclusion Criteria:

1. The participant has previously participated in this study.

2. The participant has a history of severe drug allergy or hypersensitivity, or known hypersensitivity to any of the excipients of the investigational medicinal product (IMP).

3. The participant has known hypersensitivity to duloxetine.

4. The participant has hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrose-isomaltase insufficiency.

5. The participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (e.g., spouse, parent, child, sibling) or may consent under duress.

6. The participant has a score ≥70 on the DSST (numbers correct) at the Baseline Visit.

7. The participant is, in the opinion of the investigator, not able to complete the neuropsychological tests validly at the Baseline Visit.

8. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 30 days after participating in this study; or intending to donate ova during such time period.

9. The participant has 1 or more of the following:

10. Any current psychiatric disorder other than MDD as defined in the DSM-IV-TR (as assessed by the MINI Version 6.0.0).

11. Current or history of attention deficit hyperactivity disorder (ADHD), pervasive developmental disorder, manic or hypomanic episode, schizophrenia, or any other psychotic disorder, including major depression with psychotic features, mental retardation, organic mental disorders, or mental disorders due to a general medical condition as defined in the DSM-IV-TR.

12. Current diagnosis of alcohol or other substance abuse or dependence (excluding nicotine or caffeine) as defined in the DSM-IV-TR that has not been in sustained full remission for at least 2 years prior to Screening. (Participant must also have negative urine drug screen prior to Baseline).

13. Presence or history of a clinically significant neurological disorder (including epilepsy).

14. Neurodegenerative disorder (Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, etc).

15. Any DSM-IV Axis II disorder that might compromise the study.

16. The participant has any other disorder for which the treatment takes priority over treatment of MDD or is likely to interfere with study treatment or impair treatment compliance.

17. The participant has physical, cognitive, or language impairment of such severity as to adversely affect the validity of the data derived from the neuropsychological tests.

18. The participant is diagnosed with reading disability (dyslexia).

19. The participant has a significant risk of suicide according to the investigator's clinical judgment or has a score ≥5 on item 10 (suicidal thoughts) of the MADRS or has made a suicide attempt in the previous 6 months.

20. The participant, in the opinion of the investigator, poses a risk of harm to others.

21. The participant has initiated formal cognitive or behavioral therapy, systemic psychotherapy within less than 6 months of study screening, or has plans to initiate such therapy during the study.

22. The participant has received electroconvulsive therapy, vagal nerve stimulation, or repetitive transcranial magnetic stimulation within 6 months prior to Screening.

23. The current depressive symptoms are considered by the investigator to have been resistant to 2 adequate antidepressant treatments of at least 6 weeks duration each at the recommended dose.

24. The participant has a history of moderate or severe head trauma (for example, loss of consciousness for more than 1 hour) or other neurological disorders or systemic medical diseases that are, in the opinion of the investigator, likely to affect central nervous system functioning.

25. The participant has a previous history of cancer that had been in remission for less than 5 years prior to the first dose of investigational drug. This criterion does not include those participants with basal cell or stage I squamous cell carcinoma of the skin.

26. The participant has a clinically significant unstable illness, for example, hepatic impairment or renal insufficiency, or cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic, infectious, skin and subcutaneous tissue disorders, or metabolic disturbance.

Note: For the purposes of this protocol, the following conditions are considered unstable due to the potential impact on assessment of MDD response and/or cognitive status: pain disorders, chronic fatigue syndrome, fibromyalgia, obstructive sleep apnea, and known cases of HIV, HBV, and HCV

1. The participant has a known history of or currently has increased intraocular pressure or is at risk of acute narrow-angle glaucoma.

2. The participant is required to take excluded medications or it is anticipated that the participant will require treatment with at least 1 of the disallowed concomitant medications during the study evaluation period as specified in the Excluded Medications Section.

3. The participant has received any investigational compound <30 days before Screening or 5 half-lives prior to Screening.

4. The participant has clinically significant abnormal vital signs as determined by the investigator.

5. The subject has thyroid stimulating hormone (TSH) outside the normal range at the Screening Visit.

Note: If TSH value is outside the normal range, a free T4 will be obtained. Subjects who have elevated TSH but normal T4 (i.e. subclinical hypothyroidism) will be excluded. For subjects who are on thyroid hormone replacement therapy, a lower TSH with normal T4, are eligible to participate in the study only if there are no clinical symptoms of hypothyroidism .

1. The participant has 1 or more laboratory value outside the normal range, based on the blood or urine samples taken at the Screening Visit, that are considered by the investigator to be clinically significant; or the participant has any of the following values at the Screening Visit:

2. A serum creatinine value >1.5 times the upper limits of normal (×ULN).

3. A total serum total bilirubin value >1.5×ULN.

4. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value

2×ULN.

1. The participant has an abnormal electrocardiogram (ECG) as determined by the central reader and confirmed as clinically significant by the investigator.

2. The participant has a disease or takes medication that, in the opinion of the investigator, could interfere with the assessments of safety, tolerability, or efficacy.

3. The participant, in the opinion of the investigator, is unlikely to comply with the clinical study protocol or is unsuitable for any reason.

4. The participant has been previously exposed to LuAA21004 compound.

5. The participant has a history of lack of response to previous adequate treatment with duloxetine.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Tucson	Arizona	United States
2		Little Rock	Arkansas	United States
3		Bellflower	California	United States
4		Carson	California	United States
5		Cerritos	California	United States
6		Glendale	California	United States
7		Imperial	California	United States
8		Los Angeles	California	United States
9		Norwalk	California	United States
10		Oakland	California	United States
11		Paramount	California	United States
12		San Bernardino	California	United States
13		Santa Ana	California	United States
14		Wildomar	California	United States
15		Colorado Springs	Colorado	United States
16		Denver	Colorado	United States
17		Norwalk	Connecticut	United States
18		Lauderhill	Florida	United States
19		Miami	Florida	United States
20		Orlando	Florida	United States
21		Sanford	Florida	United States
22		St. Petersburg	Florida	United States
23		Tampa	Florida	United States
24		West Palm Beach	Florida	United States
25		Chicago	Illinois	United States
26		Hoffman Estates	Illinois	United States
27		Naperville	Illinois	United States
28		Oak Brook	Illinois	United States
29		Skokie	Illinois	United States
30		Indianapolis	Indiana	United States
31		Prairie Village	Kansas	United States
32		Shreveport	Louisiana	United States
33		Baltimore	Maryland	United States
34		Haverhill	Massachusetts	United States
35		St. Louis	Missouri	United States
36		North Platte	Nebraska	United States
37		Las Vegas	Nevada	United States
38		Buffalo	New York	United States
39		New York	New York	United States
40		Staten Island	New York	United States
41		Avon lake	Ohio	United States
42		Beachwood	Ohio	United States
43		Garfield Heights	Ohio	United States
44		Toledo	Ohio	United States
45		Oklahoma City	Oklahoma	United States
46		Portland	Oregon	United States
47		Allentown	Pennsylvania	United States
48		Norristown	Pennsylvania	United States
49		Philadelphia	Pennsylvania	United States
50		Columbia	South Carolina	United States
51		Franklin	Tennessee	United States
52		Memphis	Tennessee	United States
53		Dallas	Texas	United States
54		Houston	Texas	United States
55		San Antonio	Texas	United States
56		The Woodlands	Texas	United States
57		Orem	Utah	United States
58		Salt Lake City	Utah	United States
59		Kirkland	Washington	United States
60		Seattle	Washington	United States
61		Brown Deer	Wisconsin	United States
62		Milwaukee	Wisconsin	United States
63		Kazanlak		Bulgaria
64		Novi Iskar		Bulgaria
65		Pleven		Bulgaria
66		Plovdiv		Bulgaria
67		Sofia		Bulgaria
68		Tzerova Koria		Bulgaria
69		Helsinki		Finland
70		Kuopio		Finland
71		Turku		Finland
72		Berlin		Germany
73		Bochum		Germany
74		Chemnitz		Germany
75		Hannover		Germany
76		Munchen		Germany
77		Schwerin		Germany
78		Westerstede		Germany
79		Wiesbaden		Germany
80		Bialystok		Poland
81		Leszno		Poland
82		Lodz		Poland
83		Torun		Poland
84		Ekaterinburg		Russian Federation
85		Nizhny Novgorod		Russian Federation
86		Saint-Petersburg		Russian Federation
87		Smolensk		Russian Federation
88		Stavropol		Russian Federation
89		Kharkiv		Ukraine
90		Kyiv		Ukraine
91		Luhansk		Ukraine
92		Ternopil		Ukraine

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Senior Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01564862
• Other Study ID Numbers: LuAA21004_202; 2011-005298-22; U1111-1126-0091
• First Posted: Mar 28, 2012
• Last Update Posted: Feb 5, 2015
• Last Verified: Feb 1, 2015

• Keywords provided by Takeda: Drug Therapy
• Additional relevant MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Cognitive Dysfunction; Duloxetine Hydrochloride; Vortioxetine

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 80 investigative sites in Bulgaria, Finland, Germany, Poland, Russia Federation, Ukraine.and the United States from 09 April 2012 to 05 February 2014
Pre-assignment Detail	Participants with a diagnosis of major depressive disorder were enrolled equally in 1 of 3 treatment groups, once a day placebo, 10 to 20 mg flexible dose of vortioxetine, or 60 mg duloxetine.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Period Title: Overall Study
STARTED	198	210	194
Received Treatment	196	207	191
COMPLETED	168	176	164
NOT COMPLETED	30	34	30

Baseline Characteristics

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo	Total
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).	Total of all reporting groups
Overall Participants	198	210	194	602
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.2 (12.21)	45.7 (11.46)	45.0 (12.07)	45.0 (11.90)
Age, Customized (participants) [Number]
≤ 55 years	158 79.8%	164 78.1%	152 78.4%	474 78.7%
> 55 years	40 20.2%	46 21.9%	42 21.6%	128 21.3%
Sex: Female, Male (Count of Participants)
Female	135 68.2%	138 65.7%	119 61.3%	392 65.1%
Male	63 31.8%	72 34.3%	75 38.7%	210 34.9%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	8 4%	7 3.3%	15 7.7%	30 5%
Non-Hispanic and Non- Latino	90 45.5%	104 49.5%	82 42.3%	276 45.8%
Not-Specified	100 50.5%	99 47.1%	97 50%	296 49.2%
Race/Ethnicity, Customized (participants) [Number]
Caucasian (or White, including Hispanic)	169 85.4%	176 83.8%	171 88.1%	516 85.7%
Black	28 14.1%	27 12.9%	20 10.3%	75 12.5%
Asian	1 0.5%	6 2.9%	1 0.5%	8 1.3%
American Indian or Alaska Native	0 0%	1 0.5%	2 1%	3 0.5%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	168.2 (9.17)	169.7 (9.14)	169.0 (9.43)	169.0 (9.25)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	81.84 (22.068)	81.68 (20.965)	80.96 (20.316)	81.50 (21.099)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	28.86 (7.334)	28.39 (7.312)	28.27 (6.354)	28.51 (7.018)
Smoking Classification (participants) [Number]
Never Smoked	95 48%	109 51.9%	105 54.1%	309 51.3%
Current Smoker	73 36.9%	68 32.4%	56 28.9%	197 32.7%
Past Smoker	30 15.2%	33 15.7%	33 17%	96 15.9%
Alcohol Consumption (participants) [Number]
Never	89 44.9%	84 40%	87 44.8%	260 43.2%
Once Monthly or Less Often	67 33.8%	73 34.8%	51 26.3%	191 31.7%
Once a Week	23 11.6%	31 14.8%	29 14.9%	83 13.8%
2 to 6 Times per Week	15 7.6%	19 9%	24 12.4%	58 9.6%
Daily	4 2%	3 1.4%	3 1.5%	10 1.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 8 in the Digit Symbol Substitution Test (DSST)
Description	The DSST assesses relative contributions of speed, memory, executive function and visual scanning. Participants are required to copy symbols that are paired with simple geometric shapes or numbers within a specific time for a total possible score of 0 to 133. Higher scores-correct number of symbols reflects greater objective cognitive functioning. An increase in score represents an improvement in an integrated measure of cognitive function. An Analysis of Covariance (ANCOVA) model was used with treatment and center as fixed factors and the Baseline value as a covariate.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all randomized participants who received at least one dose of study drug and had at least 1 valid post-baseline value for assessment of primary efficacy. Participants with scores of > 70 at Baseline were excluded.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Measure Participants	175	187	167
Least Squares Mean (Standard Error) [Correct symbols]	4.60 (0.530)	4.06 (0.511)	2.85 (0.542)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vortioxetine (Lu AA21004), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	P-value was from an ANCOVA model with treatment and center as fixed factors and the baseline value as a covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.75
	Confidence Interval	(2-Sided) 95%; 0.28 to 3.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.744
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.099
	Comments	P-value was from an ANCOVA model with treatment and center as fixed factors and the baseline value as a covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.21
	Confidence Interval	(2-Sided) 95%; -0.23 to 2.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.733
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Vortioxetine (Lu AA21004), Duloxetine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.460
	Comments	P-value was from an ANCOVA model with treatment and center as fixed factors and the baseline value as a covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; -0.89 to 1.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.725
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Week 8 in the Perceived Deficits Questionnaire (PDQ) Attention/Concentration and Planning/Organization Subscore
Description	PDQ is a patient-rated scale designed to subjectively assess cognitive dysfunction, comprising four 5-item subscales: Attention/Concentration, Retrospective Memory, Prospective Memory, and Planning/Organization for a total possible score of 0 to 40. The subscale Attention/Concentration is the sum of items 1, 5, 9, 13, and 17 with a range of 0-20; while the subscale Planning/Organization is the sum of items 4, 8, 12, 16, and 20 with the score range of 0 to 20. The scores of the subscales Attention/Concentration and Planning/Organization were summed. Higher scores reflect greater participant-perceived cognitive dysfunction in the domains identified. A decrease in score represents an improvement in subjective cognitive function in the domains identified. A Mixed Model Repeated Measures (MMRM) model was used with baseline*week, center, week, treatment and week*treatment as factors in the analysis.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug and had at least 1 valid post-baseline value for assessment of primary efficacy,with data available for analysis.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Measure Participants	169	179	160
Least Squares Mean (Standard Error) [score on a scale]	-8.9 (0.55)	-9.3 (0.53)	-6.3 (0.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vortioxetine (Lu AA21004), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	P-value was from a MMRM model with baseline*week, center, week, treatment and week*treatment as factors in the analysis.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -4.1 to -1.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.78
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value was from a MMRM model with baseline*week, center, week, treatment and week*treatment as factors in the analysis.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.0
	Confidence Interval	(2-Sided) 95%; -4.5 to -1.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.77
	Estimation Comments

3. Secondary Outcome

Title	Clinical Global Impressions-Improvement (CGI-I) Score at Week 8
Description	The CGI-I assesses the clinician's impression of the subject's state of mental illness improvement and consists of one question for the investigator: "Compared to his condition at the start of the study, how much has this patient changed?" which is rated on a seven-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change relative to baseline; 5=minimally worse; 6= much worse; 7=very much worse). Higher scores indicate greater worsening of illness. Values closest to 1 for this outcome measure indicate the greatest improvement of symptoms. A MMRM model was used with baseline*week, center, week, treatment and week*treatment as factors in the analysis.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug and had at least 1 valid post-baseline value for assessment of primary efficacy, with data available for analysis.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Measure Participants	169	179	161
Least Squares Mean (Standard Error) [score on a scale]	2.349 (0.0852)	2.235 (0.0826)	2.639 (0.0872)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vortioxetine (Lu AA21004), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments	P-value was from a MMRM model with baseline*week, center, week, treatment and week*treatment as factors in the analysis.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-0.290
	Confidence Interval	(2-Sided) 95%; -0.528 to -0.052
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1211
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value was from a MMRM model with baseline*week, center, week, treatment and week*treatment as factors in the analysis.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.404
	Confidence Interval	(2-Sided) 95%; -0.638 to -0.169
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1194
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline to Week 8 in the Trail Making Test (TMT-A)
Description	The TMT is a two-part cognitive test. TMT-A assesses cognitive processing speed and consists of 25 circles distributed over a sheet of paper. Participants have 4 minutes to connect the circles as quickly as possible, without lifting the pen or pencil from the paper. Tester informs participant immediately whenever they make an error and allows for corrections by participants. Lower scores represent better speed of processing. A decrease in score over the study represents an improvement in speed in processing. An ANCOVA model was used with treatment and center as fixed factors and the baseline value as a covariate.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug and had at least 1 valid post-baseline value for assessment of primary efficacy, with data available for analysis.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Measure Participants	173	180	162
Least Squares Mean (Standard Error) [seconds]	-7.70 (0.980)	-8.06 (0.955)	-6.65 (1.009)

5. Secondary Outcome

Title	Change From Baseline to Week 8 in the Trail Making Test B (TMT-B)
Description	The TMT is a two-part cognitive test. TMT-B assesses executive functioning and consists of 25 circles distributed over a sheet of paper. Participants have 4 minutes to connect the circles as quickly as possible, without lifting the pen or pencil from the paper. Tester informs participant immediately whenever they make an error and allows for corrections by participants. Lower score for TMT-B represents better executive function. A decrease in score over the study represents an improvement in executive function. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug and had at least 1 valid post-baseline value for assessment of primary efficacy, with data available for analysis.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Measure Participants	157	170	157
Least Squares Mean (Standard Error) [seconds]	-18.73 (2.096)	-14.60 (2.011)	-9.06 (2.101)

6. Secondary Outcome

Title	Change in Time From Baseline to Week 8 in the Stroop Test
Description	The STROOP test assesses the ability to inhibit a prepotent response to reading words while performing a task that requires attention control. It comprises of 2 sheets with 50 words each, up to 50 correct responses for each of the congruent and incongruent Stroop tests. Participants have 4 minutes to name the ink color of each word. Lower time to complete the test indicates better performance. Higher number of correct responses indicates better responses. A decrease in the time to complete the tests and an increase in the number of correct responses both indicate improvement over the course of the study. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug and had at least 1 valid post-baseline value for assessment of primary efficacy, with data available for analysis.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Measure Participants	175	187	167
Congruent (n=174,187,167)	-3.30 (1.086)	-4.54 (1.044)	-4.37 (1.105)
Incongruent (n=172,186,166)	-8.17 (1.560)	-9.83 (1.498)	-8.11 (1.586)

7. Secondary Outcome

Title	Change From Baseline to Week 8 in the Groton Maze Learning Test (GMLT)
Description	The GMLT measures executive functioning and spatial problem solving. Participants learn a hidden pathway through a maze of 10 x 10 grid of tiles on a computer touch screen using step-by-step guess, with trial and error feedback after each step. Once the pathway is learned, participants repeat the same pathway four more times. It usually takes 5-6 minutes to administer this test. Lower score equals better performance. A decrease in score over the course of the study indicates improved executive function. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug and had at least 1 valid post-baseline value for assessment of primary efficacy, with data available for analysis.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Measure Participants	169	179	159
Least Squares Mean (Standard Error) [Errors]	-5.43 (1.355)	-5.16 (1.314)	-3.49 (1.397)

8. Secondary Outcome

Title	Change From Baseline to Week 8 in the Detection Task (DT)
Description	The DT is a computerized test that measures simple reaction time and psychomotor speed. The task requires participants to respond by pressing a "yes" button as soon as an onscreen playing card is turned over and is red, and by pressing a "no" button if the card is not red. It takes 2 minutes to be administered. There is no minimum or maximum scores since it is a time-based assessment. Lower score equals better performance. A decrease in score over the course of the study indicates improved speed of processing and psychomotor function. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug and had at least 1 valid post-baseline value for assessment of primary efficacy, with data available for analysis.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Measure Participants	175	182	167
Least Squares Mean (Standard Error) [Log10 milliseconds]	-0.050 (0.0080)	-0.039 (0.0078)	-0.033 (0.0082)

9. Secondary Outcome

Title	Change From Baseline to Week 8 in the Identification Task (IT)
Description	The IT measured choice reaction time: the participant pressed a "yes" button whenever an onscreen playing card turned face up and was red, or a "no" button if the card was not red. The IT took on average 2 minutes to complete. Lower scores equal better performance. A decrease in score over the course of the study indicates improved visual attention/vigilance. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug and had at least 1 valid post-baseline value for assessment of primary efficacy, with data available for analysis.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Measure Participants	175	182	167
Least Squares Mean (Standard Error) [Log10 milliseconds]	-0.037 (0.0060)	-0.030 (0.0059)	-0.024 (0.0062)

10. Secondary Outcome

Title	Change From Baseline to Week 8 in the One-Back Task
Description	The One-Back test measures the cognitive domain of attention and working memory through yes or no responses to 30 trials. The task requires participants to report when a stimulus item presented serially is the same as an item one step back from the item at hand for a total correct responses 0 to 100. It usually takes 2-3 minutes to be administered. Higher scores equal better performance. An increase in score over the course of the study indicates improved attention/working memory. An ANCOVA model was used with treatment and center as fixed factors and the Baseline value as a covariate.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug and had at least 1 valid post-baseline value for assessment of primary efficacy, with data available for analysis.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Measure Participants	175	182	167
Least Squares Mean (Standard Error) [Log 10 milliseconds]	-0.028 (0.0062)	-0.024 (0.0060)	-0.022 (0.0063)

11. Secondary Outcome

Title	Proportion of Cognitive Dysfunction Improvement Due to Improvement of Depression
Description	Improvement of Cognitive Dysfunction is determined using the change from Baseline to Week 8 in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score and the Digital Symbol Substitution Test (DSST) total number of correct symbols. The MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression). The DSST assesses relative contributions of speed, memory, executive function and visual scanning. The proportion of direct effect from treatment = DSST difference / (DSST difference + coefficient*MADRS difference).
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid post-baseline value for assessment.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.
Measure Participants	175	187
Number [proportion of direct effect]	75.66	48.69

12. Secondary Outcome

Title	Change From Baseline to Week 8 in the MADRS Total Score
Description	MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. A negative change from Baseline indicates improvement.
Time Frame	Baseline, Week 1, Week 4 and Week 8

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all randomized participants who received at least one dose of study drug and had at least 1 valid post-baseline value for assessment of primary efficacy. Last Observation Carried Forward.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Measure Participants	175	187	167
Change at Week 1	-3.7 (4.80)	-4.6 (5.29)	-3.4 (5.03)
Change at Week 4	-9.8 (6.85)	-11.6 (7.94)	-8.0 (7.98)
Change at Week 8	-14.3 (8.97)	-15.5 (9.23)	-12.3 (9.64)

13. Secondary Outcome

Title	Percentage of Participants With MADRS Response at Week 8
Description	MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. MADRS Response was defined as a ≥50% decrease in MADRS Total Score from Baseline.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all randomized participants who received at least one dose of study drug and had at least 1 valid post-baseline value for assessment of primary efficacy. Last Observation Carried Forward.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Measure Participants	175	187	167
Number [percentage of participants]	50.9 25.7%	54.5 26%	41.3 21.3%

14. Secondary Outcome

Title	Percentage of Participants in MADRS Remission at Week 8
Description	MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. MADRS Remission was defined as a MADRS total score ≤10.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all randomized participants who received at least one dose of study drug and had at least 1 valid post-baseline value for assessment of primary efficacy. Last Observation Carried Forward.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Measure Participants	175	187	167
Number [percentage of participants]	30.3 15.3%	33.7 16%	21.6 11.1%

15. Secondary Outcome

Title	Change From Baseline to Week 8 in the Clinical Global Impressions-Severity (CGI-S) Score
Description	The CGI-S assesses the clinician's impression of the subject's current state of mental illness and consists of one question for the investigator: "Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?" which is rated on a seven-point scale (1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill). A MMRM model with baseline*week, center, week, treatment and week*treatment as factors was used for analyses.
Time Frame	Baseline, Week 1, Week 4 and Week 8

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug and had at least 1 valid post-baseline value for assessment of primary efficacy,with data available for analysis. Repeated Measures Analysis.

Arm/Group Title	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.	Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.	Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
Measure Participants	175	187	167
Change from Baseline at Week 1 (n=174, 187,167)	-0.289 (0.0426)	-0.353 (0.0410)	-0.243 (0.0435)
Change from Baseline at Week 4 (n=173,184,165)	-0.951 (0.0678)	-1.170 (0.0656)	-0.617 (0.0693)
Change from Baseline at Week 8 (n=169,179,161)	-1.546 (0.0886)	-1.698 (0.0859)	-1.225 (0.0906)

Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events that started after the first dose of study drug and no more than 30 days after the last dose of study drug (Up to 12 Weeks)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Vortioxetine (Lu AA21004)		Duloxetine		Placebo
Arm/Group Description	Vortioxetine (Lu AA21004) 10 mg, capsules, orally, once daily for one week; then dose adjustment to a maximum 20 mg, capsules, orally, once daily for up to 7 weeks.		Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.		Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).
All Cause Mortality
	Vortioxetine (Lu AA21004)		Duloxetine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Vortioxetine (Lu AA21004)		Duloxetine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/196 (0.5%)		1/207 (0.5%)		2/191 (1%)
Cardiac disorders
Acute myocardial infarction	0/196 (0%)		0/207 (0%)		1/191 (0.5%)
Injury, poisoning and procedural complications
Craniocerebral injury	0/196 (0%)		1/207 (0.5%)		0/191 (0%)
Subdural haematoma	0/196 (0%)		1/207 (0.5%)		0/191 (0%)
Psychiatric disorders
Depression	0/196 (0%)		0/207 (0%)		1/191 (0.5%)
Suicide attempt	1/196 (0.5%)		0/207 (0%)		0/191 (0%)
Other (Not Including Serious) Adverse Events
	Vortioxetine (Lu AA21004)		Duloxetine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	73/196 (37.2%)		84/207 (40.6%)		41/191 (21.5%)
Gastrointestinal disorders
Nausea	40/196 (20.4%)		43/207 (20.8%)		8/191 (4.2%)
Diarrhoea	11/196 (5.6%)		6/207 (2.9%)		5/191 (2.6%)
Dry mouth	6/196 (3.1%)		16/207 (7.7%)		9/191 (4.7%)
Infections and infestations
Nasopharyngitis	7/196 (3.6%)		8/207 (3.9%)		11/191 (5.8%)
Metabolism and nutrition disorders
Decreased appetite	3/196 (1.5%)		12/207 (5.8%)		1/191 (0.5%)
Nervous system disorders
Headache	20/196 (10.2%)		24/207 (11.6%)		16/191 (8.4%)
Dizziness	6/196 (3.1%)		11/207 (5.3%)		5/191 (2.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.