A Phase 3 Study of Lu AA21004 in Patients With Major Depressive Disorder

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02389816
• Collaborator: (none)
• Enrollment: 493
• Locations: 47
• Arms: 3
• Actual Duration (Months): 35.2
• Patients Per Site: 10.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of two fixed doses of vortioxetine (Lu AA21004; 10 or 20 mg/day) after 8 weeks of treatment in patients with major depressive disorder (MDD) in Japan.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Placebo; Drug: Vortioxetine	Phase 3

Detailed Description

This is a randomized, double-blind, placebo-controlled, parallel-group, phase III study to assess the efficacy and safety of 8-week treatment of two fixed doses of Vortioxetine (Lu AA21004; 10 or 20 mg/day) in Japanese participants with major depressive disorder (MDD).

Study Design

• Study Type: Interventional
• Actual Enrollment: 493 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase III Study to Evaluate the Efficacy and Safety of Once Daily Oral Lu AA21004 in Patients With Major Depressive Disorder
• Actual Study Start Date: Apr 10, 2015
• Actual Primary Completion Date: Mar 16, 2018
• Actual Study Completion Date: Mar 16, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo tablets, orally, once daily for up to Week 8	Drug: Placebo; Placebo tablets
Experimental: Vortioxetine 10 mg Vortioxetine 10 mg tablets, orally, once daily for up to Week 8	Drug: Vortioxetine; Vortioxetine tablets; Other Names: Lu AA21004
Experimental: Vortioxetine 20 mg Vortioxetine 10 mg tablets, orally, once daily for up to Week 1 followed by vortioxetine 20 mg tablets, orally, once daily for up to Week 8	Drug: Vortioxetine; Vortioxetine tablets; Other Names: Lu AA21004

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score to Week 8 [Baseline (At the start of double-blind treatment period), up to 8 weeks]

   MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension). MADRS corresponds to core symptoms of depression, and 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.

Secondary Outcome Measures

1. MADRS Response at Week 8 (Last Observation Carried Forward (LOCF)) [Week 8]

   Reported data was percentage of participants who met MADRS response criteria (defined as a ≥50% decrease in the MADRS total score from Baseline) at Week 8 for each group. MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension). MADRS corresponds to core symptoms of depression, and 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.

2. MADRS Remission at Week 8 (LOCF) [Week 8]

   Reported data was percentage of participants who met MADRS remission criteria (defined as a MADRS total score ≤10) at Week 8 for each group. MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension). MADRS corresponds to core symptoms of depression, and 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.

3. Change From Baseline in Hamilton Depression Scale (HAM-D17) Total Score to Week 8 (LOCF) [Baseline (At the start of double-blind treatment period), up to 8 weeks]

   The HAM-D17 is a clinician-rated scale for assessing the severity of depression symptoms. The scores for each item range from 0 to 4 or 0 to 2, where 0 represents no symptoms. The rating is based on the past 7 days prior to the time of assessment. The total score ranges from 0 to 52 where a higher score indicates a greater depressive state.

4. Clinical Global Impressions-Improvement (CGI-I) Score at Week 8 (LOCF) [Week 8]

   The CGI-I assesses the participant's state of mental illness improvement. The participant's condition compared to baseline is rated on a seven-point scale (1=very much improved ~ 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.

5. Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score to Week 8 (LOCF) [Baseline (At the start of double-blind treatment period), up to 8 weeks]

   The CGI-S assesses the impression of the participant's current state of mental illness. The current severity of mental illness is rated on a seven-point scale (1=normal, not ill at all ~ 7=most extremely ill) based on a total clinical experience. Higher scores indicate greater severity of mental illness.

6. Change From Baseline in Sheehan Disability Scale (SDS) Total Score to Week 8 (LOCF) [Baseline (At the start of double-blind treatment period), up to 8 weeks]

   The SDS assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment.

7. Change From Baseline in Digit Symbol Substitution Test (DSST) Total Score to Week 8 (LOCF) [Baseline (At the start of double-blind treatment period), up to 8 weeks]

   The DSST is a neuropsychological test to assess cognitive function. 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.

8. Change From Baseline in Perceived Deficits Questionnaire (PDQ-5) Total Score to Week 8 (LOCF) [Baseline (At the start of double-blind treatment period), up to 8 weeks]

   PDQ-5 is a self-administered 5-item questionnaire to assess cognition function, including subscales of attention/concentration, retrospective memory, prospective memory, and planning/organization. PDQ-5 total score ranges from 0 to 20 with smaller scores indicate greater cognitive function.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

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

2. The participant signs and dates a written, informed consent form prior to the initiation of any study procedures.

3. The participant suffers from recurrent MDD as the primary diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria (classification code 296.3x).

4. The participant is a man or a woman aged 20 to 75 years (both inclusive) at the time of informed consent.

5. The reported duration of the current major depressive episode is 3 to 12 months (both inclusive) at the start of screening period.

6. The participant has a MADRS total score ≥26, Hamilton Depression Rating Scale (HAM-D17) total score ≥18, and Clinical global impression scale-Severity (CGI-S) score ≥4 at the start of screening period, at the start of placebo lead-in period and at the start of double-blind treatment period.

7. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent to the end of the follow-up period.

Exclusion Criteria:

1. The participant has any following current or past history of psychiatric disorder and/or neurological disorder:

• Any current psychiatric disorder other than MDD as defined by DSM-IV-TR (To be assessed by Mini International Neuropsychiatric Interview: MINI). A participant who exhibits symptoms of anxiety is eligible unless the participant fulfills the diagnostic criteria for a current anxiety disorder per DSM-IV-TR.

• Current diagnosis or history of manic, mixed or hypomanic episode, MDD with psychotic features, schizophrenia or any other psychotic disorder (including substance-related mental disorders, or mental disorders due to a general medical condition) as defined by DSM-IV-TR.

• Current diagnosis or history of any substance-related disorder (except nicotine and caffeine-related disorders) as defined by DSM-IV-TR.

• The participant with a positive urine drug screening result at the start of screening period or the start of placebo lead-in period. In case that a participant showed positive test result at the start of screening period because the test was conducted before washout of pretreatment drug, the participant is eligible as long as he/she shows negative result at the start of placebo lead-in period.

• Presence or history of any clinically significant neurological disorder (including epilepsy).

• Any neurodegenerative disorder (e.g. Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease).

• Any DSM-IV-TR axis II disorder.

1. The participant has the current or previous major depressive episode which was considered by the investigator or sub-investigator to have been resistant to 2 or more adequate antidepressants treatments of at least 6 weeks duration each at sufficient doses.

2. The participant has received any augmentation therapy (e.g. lithium, T3/T4, lamotrigine, sodium valproate, carbamazepine, additional atypical antipsychotic, or concomitant use of other antidepressant, etc.) for the current major depressive episode.

3. In the opinion of the investigator or sub-investigator, the participant has experienced significant number of major depressive episodes in the past, and is suspected of disease other than MDD.

4. In the opinion of the investigator or sub-investigator, the participant has experienced the first major depressive episode at his/her young age, and is suspected of disease other than MDD.

5. The participant has a MADRS total score at the start of double-blind treatment period that has improved or aggravated by 25% or more from the score at the start of placebo lead-in period.

6. The participant is significantly non-compliant with the study drug in the placebo lead-in period; e.g., not taking the study drug for 6 or more consecutive days.

7. The participant has received electroconvulsive therapy, vagus nerve stimulation, or repetitive transcranial magnetic stimulation therapy within 6 months prior to the screening period, or plans to initiate such therapy during the study.

8. The participant is receiving cognitive-behavioral therapy or psychotherapy at the time of informed consent, or plans to initiate such therapy during the study.

9. The participant is at significant risk of suicide or has a score ≥5 on Item 10 (suicidal thoughts) of the MADRS at the start of screening period, at the start of placebo lead-in period or at the start of double-blind treatment period, or has attempted suicide within 6 months prior to the start of screening period.

10. The participant has experienced any environmental change (e.g. temporary retirement, returnment, change of residence) considered by the investigator or sub-investigator to have the potential to impact on the efficacy evaluation, or plans such environmental changes during the study.

11. The participant is currently receiving drug therapy for thyroid dysfunction.

12. The participant is currently receiving hormonal therapy for gynecological disease.

13. The participant has taken excluded medications during the protocol-specified period, or will require to take excluded medications during the study.

14. The participant has previously received vortioxetine.

15. The participant has received study drug in a previous clinical study of Lu AA21004 (including this study).

16. The participant has a clinically significant chronic liver disease.

17. The participant has a history of severe allergy or hypersensitivity to drugs.

18. The participant has a clinically significant unstable illness, for example, liver disorder or renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic, infectious, neoplastic, skin and subcutaneous tissue disorders, eye disorders, or metabolic disturbance.

19. The participant has clinically significant abnormal vital signs as determined by the investigator or sub-investigator at the start of screening period, placebo lead-in period, or double-blind treatment period.

20. The participant has clinically significant abnormal electrocardiogram (ECG) as determined by the investigator or sub-investigator, at the start of the screening period, at the start of placebo lead-in period, or at the start of double-blind treatment period.

21. The participant has clinically significant abnormal findings of clinical laboratory tests as determined by the investigator or sub-investigator, or has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × ULN at the start of screening period or at the start of placebo lead-in period.

22. If female, the participant is pregnant or lactating.

23. The participant has a disease or takes medications that could, in the opinion of the investigator or sub-investigator, interfere with the evaluation of the safety, tolerability, or efficacy.

24. The participant is, in the opinion of the investigator or sub-investigator, unsuitable for this study for any other reason.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Nagoya	Aichi	Japan
2		Nagareyama	Chiba	Japan
3		Noda	Chiba	Japan
4		Iizuka	Fukuoka	Japan
5		Kitakyushu	Fukuoka	Japan
6		Kurume	Fukuoka	Japan
7		Koriyama	Fukushima	Japan
8		Shirakawa	Fukushima	Japan
9		Sapporo	Hokkaido	Japan
10		Ashiya	Hyogo	Japan
11		Kanazawa	Ishikawa	Japan
12		Kawasaki	Kanagawa	Japan
13		Yokohama	Kanagawa	Japan
14		Yokosuka	Kanagawa	Japan
15		Kurashiki	Okayama	Japan
16		Kadoma	Osaka	Japan
17		Kita-ku	Osaka	Japan
18		Osakasayama	Osaka	Japan
19		Sakai	Osaka	Japan
20		Karatsu	Saga	Japan
21		Kawagoe	Saitama	Japan
22		Kusatsu	Shiga	Japan
23		Anan	Tokushima	Japan
24		Arakawa-ku	Tokyo	Japan
25		Chiyoda-ku	Tokyo	Japan
26		Hachioji	Tokyo	Japan
27		Itabashi-ku	Tokyo	Japan
28		Katsushika-ku	Tokyo	Japan
29		Koto-ku	Tokyo	Japan
30		Meguro-ku	Tokyo	Japan
31		Minato-ku	Tokyo	Japan
32		Mitaka	Tokyo	Japan
33		Musashino	Tokyo	Japan
34		Nakano-ku	Tokyo	Japan
35		Setagaya-ku	Tokyo	Japan
36		Shibuya-ku	Tokyo	Japan
37		Shinagawa-ku	Tokyo	Japan
38		Shinjuku-ku	Tokyo	Japan
39		Suginami-ku	Tokyo	Japan
40		Taito-ku	Tokyo	Japan
41		Toshima-ku	Tokyo	Japan
42		Kofu	Yamanashi	Japan
43		Fukuoka		Japan
44		Hiroshima		Japan
45		Kumamoto		Japan
46		Okayama		Japan
47		Saitama		Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Aug 18, 2015
• Statistical Analysis Plan - May 23, 2018

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02389816
• Other Study ID Numbers: LuAA21004/CCT-004; U1111-1167-1520; JapicCTI-152831
• First Posted: Mar 17, 2015
• Last Update Posted: Mar 24, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Drug therapy
• Additional relevant MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Vortioxetine

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 64 investigative sites in Japan, from 10 April 2015 to 16 March 2018.
Pre-assignment Detail	Participants with a historical diagnosis of major depressive disorder were enrolled placebo lead-in period for one week prior to randomization, after that participants randomized and enrolled in one of three treatment group (Placebo Group, vortioxetine 10 milligrams (mg) Group, vortioxetine 20 mg Group) for 8 weeks as double-blind treatment period.

Arm/Group Title	Placebo	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Placebo tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 1, followed by vortioxetine 20 mg tablets, orally, once daily for up to Week 8
Period Title: Overall Study
STARTED	164	165	164
COMPLETED	149	152	152
NOT COMPLETED	15	13	12

Baseline Characteristics

Arm/Group Title	Placebo	Vortioxetine 10 mg	Vortioxetine 20 mg	Total
Arm/Group Description	Placebo tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 1, followed by vortioxetine 20 mg tablets, orally, once daily for up to Week 8	Total of all reporting groups
Overall Participants	164	165	164	493
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	39.5 (10.47)	40.0 (10.58)	40.4 (11.31)	40.0 (10.78)
Sex: Female, Male (Count of Participants)
Female	72 43.9%	72 43.6%	80 48.8%	224 45.4%
Male	92 56.1%	93 56.4%	84 51.2%	269 54.6%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Number) [Number]
Japan	164 100%	165 100%	164 100%	493 100%
Height (Centimeters (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Centimeters (cm)]	166.5 (8.51)	165.2 (9.04)	164.5 (7.86)	165.4 (8.51)
Weight (Kilograms (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kilograms (kg)]	62.44 (12.218)	61.97 (12.958)	61.54 (12.006)	61.98 (12.382)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	22.44 (3.450)	22.56 (3.560)	22.65 (3.594)	22.55 (3.530)
Montgomery Åsberg Depression Rating Scale (MADRS) Total Score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	30.5 (3.87)	30.8 (3.73)	30.6 (3.62)	30.6 (3.73)
Hamilton Depression Scale (HAM-D17) Total Score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	22.0 (3.19)	22.1 (3.10)	22.2 (3.10)	22.1 (3.13)
Clinical Global Impressions-Severity (CGI-S) Score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	4.5 (0.63)	4.5 (0.63)	4.5 (0.61)	4.5 (0.62)
Sheehan Disability Scale (SDS) Total Score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	13.9 (6.22)	14.0 (6.00)	14.8 (5.47)	14.2 (5.91)
Digit Symbol Substitution Test (DSST) Score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	60.2 (13.93)	56.8 (15.15)	58.0 (13.72)	58.3 (14.32)
Perceived Deficits Questionnaire (PDQ-5) Score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	9.0 (3.54)	9.5 (3.52)	9.7 (3.47)	9.4 (3.52)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score to 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). MADRS corresponds to core symptoms of depression, and 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 (At the start of double-blind treatment period), up to 8 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All participants who were randomized and received at least 1 dose of the study drug in the double-blind treatment period.

Arm/Group Title	Placebo	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Placebo tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 1, followed by vortioxetine 20 mg tablets, orally, once daily for up to Week 8
Measure Participants	164	165	164
Least Squares Mean (Standard Error) [Scores on a scale]	-12.37 (0.714)	-15.03 (0.699)	-15.45 (0.705)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0080
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed Models for Repeated Measures (MMRM)
Method of Estimation	Estimation Parameter	Least square (LS) mean difference
	Estimated Value	-2.66
	Confidence Interval	(2-Sided) 95%; -4.63 to -0.70
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.999
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 20 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0023
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed Models for Repeated Measures (MMRM)
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.07
	Confidence Interval	(2-Sided) 95%; -5.05 to -1.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.003
	Estimation Comments

2. Secondary Outcome

Title	MADRS Response at Week 8 (Last Observation Carried Forward (LOCF))
Description	Reported data was percentage of participants who met MADRS response criteria (defined as a ≥50% decrease in the MADRS total score from Baseline) at Week 8 for each group. MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension). MADRS corresponds to core symptoms of depression, and 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	Week 8

Outcome Measure Data

Analysis Population Description

FAS: All participants who were randomized and received at least 1 dose of the study drug in the double-blind treatment period. Here, number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Placebo tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 1, followed by vortioxetine 20 mg tablets, orally, once daily for up to Week 8
Measure Participants	164	165	164
Number [Percentage of Participants]	36.6 22.3%	47.9 29%	50.6 30.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0341
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.621
	Confidence Interval	(2-Sided) 95%; 1.037 to 2.533
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 20 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0110
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.788
	Confidence Interval	() 95%; 1.143 to 2.799
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	MADRS Remission at Week 8 (LOCF)
Description	Reported data was percentage of participants who met MADRS remission criteria (defined as a MADRS total score ≤10) at Week 8 for each group. MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension). MADRS corresponds to core symptoms of depression, and 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	Week 8

Outcome Measure Data

Analysis Population Description

FAS: All participants who were randomized and received at least 1 dose of the study drug in the double-blind treatment period. Here, number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Placebo tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 1, followed by vortioxetine 20 mg tablets, orally, once daily for up to Week 8
Measure Participants	164	165	164
Number [Percentage of Participants]	21.1 12.9%	32.1 19.5%	30.9 18.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0186
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.839
	Confidence Interval	(2-Sided) 95%; 1.107 to 3.054
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 20 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0418
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.700
	Confidence Interval	(2-Sided) 95%; 1.020 to 2.834
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Hamilton Depression Scale (HAM-D17) Total Score to Week 8 (LOCF)
Description	The HAM-D17 is a clinician-rated scale for assessing the severity of depression symptoms. The scores for each item range from 0 to 4 or 0 to 2, where 0 represents no symptoms. The rating is based on the past 7 days prior to the time of assessment. The total score ranges from 0 to 52 where a higher score indicates a greater depressive state.
Time Frame	Baseline (At the start of double-blind treatment period), up to 8 weeks

Outcome Measure Data

Analysis Population Description

FAS: All participants who were randomized and received at least 1 dose of the study drug in the double-blind treatment period. Here, number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Placebo tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 1, followed by vortioxetine 20 mg tablets, orally, once daily for up to Week 8
Measure Participants	164	165	164
Least Squares Mean (Standard Error) [Scores on a scale]	-8.38 (0.541)	-10.19 (0.524)	-10.17 (0.532)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0165
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.81
	Confidence Interval	(2-Sided) 95%; -3.290 to -0.332
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.753
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 20 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0190
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.79
	Confidence Interval	(2-Sided) 95%; -3.278 to -0.295
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.759
	Estimation Comments

5. Secondary Outcome

Title	Clinical Global Impressions-Improvement (CGI-I) Score at Week 8 (LOCF)
Description	The CGI-I assesses the participant's state of mental illness improvement. The participant's condition compared to baseline is rated on a seven-point scale (1=very much improved ~ 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.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

FAS: All participants who were randomized and received at least 1 dose of the study drug in the double-blind treatment period. Here, number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Placebo tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 1, followed by vortioxetine 20 mg tablets, orally, once daily for up to Week 8
Measure Participants	164	165	164
Least Squares Mean (Standard Error) [Scores on a scale]	2.77 (0.085)	2.42 (0.084)	2.38 (0.085)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0031
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.36
	Confidence Interval	(2-Sided) 95%; -0.590 to -0.121
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.120
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 20 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95%; -0.629 to -0.158
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.120
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score to Week 8 (LOCF)
Description	The CGI-S assesses the impression of the participant's current state of mental illness. The current severity of mental illness is rated on a seven-point scale (1=normal, not ill at all ~ 7=most extremely ill) based on a total clinical experience. Higher scores indicate greater severity of mental illness.
Time Frame	Baseline (At the start of double-blind treatment period), up to 8 weeks

Outcome Measure Data

Analysis Population Description

FAS: All participants who were randomized and received at least 1 dose of the study drug in the double-blind treatment period. Here, number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Placebo tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 1, followed by vortioxetine 20 mg tablets, orally, once daily for up to Week 8
Measure Participants	164	165	164
Least Squares Mean (Standard Error) [Scores on a scale]	-1.19 (0.0088)	-1.42 (0.0087)	-1.48 (0.0087)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0609
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.474 to 0.011
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.123
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 20 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0179
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.537 to -0.051
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.124
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Sheehan Disability Scale (SDS) Total Score to Week 8 (LOCF)
Description	The SDS assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment.
Time Frame	Baseline (At the start of double-blind treatment period), up to 8 weeks

Outcome Measure Data

Analysis Population Description

FAS: All participants who were randomized and received at least 1 dose of the study drug in the double-blind treatment period. Here, number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Placebo tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 1, followed by vortioxetine 20 mg tablets, orally, once daily for up to Week 8
Measure Participants	164	165	164
Least Squares Mean (Standard Error) [Scores on a scale]	-2.85 (0.447)	-4.20 (0.432)	-4.43 (0.440)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0311
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.34
	Confidence Interval	(2-Sided) 95%; -2.564 to -0.122
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.621
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 20 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0126
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.57
	Confidence Interval	(2-Sided) 95%; -2.807 to -0.339
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.628
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in Digit Symbol Substitution Test (DSST) Total Score to Week 8 (LOCF)
Description	The DSST is a neuropsychological test to assess cognitive function. 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.
Time Frame	Baseline (At the start of double-blind treatment period), up to 8 weeks

Outcome Measure Data

Analysis Population Description

FAS: All participants who were randomized and received at least 1 dose of the study drug in the double-blind treatment period. Here, number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Placebo tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 1, followed by vortioxetine 20 mg tablets, orally, once daily for up to Week 8
Measure Participants	164	165	164
Least Squares Mean (Standard Error) [Scores on a scale]	4.92 (0.632)	4.13 (0.628)	4.80 (0.629)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3793
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.79
	Confidence Interval	(2-Sided) 95%; -2.539 to 0.968
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.893
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 20 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9011
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -1.862 to 1.641
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.891
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in Perceived Deficits Questionnaire (PDQ-5) Total Score to Week 8 (LOCF)
Description	PDQ-5 is a self-administered 5-item questionnaire to assess cognition function, including subscales of attention/concentration, retrospective memory, prospective memory, and planning/organization. PDQ-5 total score ranges from 0 to 20 with smaller scores indicate greater cognitive function.
Time Frame	Baseline (At the start of double-blind treatment period), up to 8 weeks

Outcome Measure Data

Analysis Population Description

FAS: All participants who were randomized and received at least 1 dose of the study drug in the double-blind treatment period. Here, number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Placebo tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 8	Vortioxetine 10 mg tablets, orally, once daily for up to Week 1, followed by vortioxetine 20 mg tablets, orally, once daily for up to Week 8
Measure Participants	164	165	164
Least Squares Mean (Standard Error) [Scores on a scale]	-1.41 (0.234)	-2.28 (0.231)	-2.69 (0.234)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0089
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.87
	Confidence Interval	(2-Sided) 95%; -1.512 to -0.218
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.329
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Vortioxetine 20 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.27
	Confidence Interval	(2-Sided) 95%; -1.922 to -0.619
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.332
	Estimation Comments

Adverse Events

Time Frame	Up to Week 12
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	Placebo		Vortioxetine 10 mg		Vortioxetine 20 mg
Arm/Group Description	Placebo tablets, orally, once daily for up to Week 8		Vortioxetine 10 mg tablets, orally, once daily for up to Week 8		Vortioxetine 10 mg tablets, orally, once daily for up to Week 1, followed by vortioxetine 20 mg tablets, orally, once daily for up to Week 8
All Cause Mortality
	Placebo		Vortioxetine 10 mg		Vortioxetine 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/161 (0%)		0/165 (0%)		2/163 (1.2%)
Serious Adverse Events
	Placebo		Vortioxetine 10 mg		Vortioxetine 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/161 (0.6%)		1/165 (0.6%)		3/163 (1.8%)
Injury, poisoning and procedural complications
Anaesthetic complication	0/161 (0%)		0/165 (0%)		1/163 (0.6%)
Subarachnoid haemorrhage	0/161 (0%)		0/165 (0%)		1/163 (0.6%)
Nervous system disorders
Altered state of consciousness	0/161 (0%)		1/165 (0.6%)		0/163 (0%)
Cerebral haemorrhage	0/161 (0%)		0/165 (0%)		1/163 (0.6%)
Renal and urinary disorders
Nephrolithiasis	1/161 (0.6%)		0/165 (0%)		0/163 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Vortioxetine 10 mg		Vortioxetine 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/161 (19.9%)		54/165 (32.7%)		51/163 (31.3%)
Gastrointestinal disorders
Nausea	1/161 (0.6%)		21/165 (12.7%)		25/163 (15.3%)
Vomiting	0/161 (0%)		9/165 (5.5%)		6/163 (3.7%)
Infections and infestations
Nasopharyngitis	26/161 (16.1%)		23/165 (13.9%)		21/163 (12.9%)
Nervous system disorders
Somnolence	6/161 (3.7%)		7/165 (4.2%)		11/163 (6.7%)

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.