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Clinical Trial Results:
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)

Summary
EudraCT number	2011-005298-22
Trial protocol	DE FI BG
Global end of trial date	05 Feb 2014

Results information
Results version number	v1(current)
This version publication date	04 Mar 2016
First version publication date	28 May 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

Lu_AA21004_202

ISRCTN number

US NCT number

NCT01564862

WHO universal trial number (UTN)

U1111-1126-0091

Sponsor organisation name

Takeda

Sponsor organisation address

One Takeda Parkway, Deerfield, IL, United States, 60015

Public contact

Clinical Study Manager, Takeda Global Research & Development Centre (Europe) Ltd, 44 (0)2031168000, clinicaloperations@tgrd.com

Scientific contact

Clinical Study Manager, Takeda Global Research & Development Centre (Europe) Ltd, 44 (0)2031168000, clinicaloperations@tgrd.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

24 Jul 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

13 Jan 2014

Global end of trial reached?

Yes

Global end of trial date

05 Feb 2014

Was the trial ended prematurely?

Main objective of the trial

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 (MDD).

Protection of trial subjects

All study participants were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Apr 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Ukraine: 19

Country: Number of subjects enrolled

Poland: 40

Country: Number of subjects enrolled

Bulgaria: 127

Country: Number of subjects enrolled

Finland: 9

Country: Number of subjects enrolled

Germany: 90

Country: Number of subjects enrolled

Russian Federation: 11

Country: Number of subjects enrolled

United States: 306

Worldwide total number of subjects

602

EEA total number of subjects

266

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

597

From 65 to 84 years

85 years and over

Subject disposition

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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.

Screening details

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.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Vortioxetine (Lu AA21004)

Arm 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.

Arm type

Experimental

Investigational medicinal product name

Vortioxetine

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Vortioxetine capsules

Duloxetine

Arm description

Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.

Arm type

Active comparator

Investigational medicinal product name

Duloxetine

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Duloxetine capsules

Placebo

Arm description

Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Placebo matching capsules

Number of subjects in period 1	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Started	198	210	194
Received Treatment	196	207	191
Completed	168	176	164
Not completed	30	34	30
Major Protocol Deviation	3	3	4
Voluntary Withdrawal	9	6	8
Other Reasons	1	-	-
Pretreatment Event or Adverse Event	6	12	6
Lost to follow-up	10	8	6
Lack of efficacy	1	5	6

Baseline characteristics

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Reporting group title

Vortioxetine (Lu AA21004)

Reporting 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.

Reporting group title

Duloxetine

Reporting group description

Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.

Reporting group title

Placebo

Reporting group description

Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).

Reporting group values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo	Total
Number of subjects	198	210	194	602
Age categorical
Units: Subjects
≤ 55 years	158	164	152	474
> 55 years	40	46	42	128
Age continuous
Units: years
arithmetic mean (standard deviation)	44.2 ( 12.21 )	45.7 ( 11.46 )	45 ( 12.07 )	-
Gender categorical
Units: Subjects
Female	135	138	119	392
Male	63	72	75	210
Race/Ethnicity
Units: Subjects
Hispanic or Latino	8	7	15	30
Non-Hispanic and Non-Latino	90	104	82	276
Not-Specified	100	99	97	296
Race/Ethnicity
Units: Subjects
Caucasian (or White, including Hispanic)	169	176	171	516
Black	28	27	20	75
Asian	1	6	1	8
American Indian or Alaska Native	0	1	2	3
Smoking Classification
Units: Subjects
Never Smoked	95	109	105	309
Current Smoker	73	68	56	197
Past Smoker	30	33	33	96
Alcohol Consumption
Units: Subjects
Never	89	84	87	260
Once Monthly or Less Often	67	73	51	191
Once a Week	23	31	29	83
2 to 6 Times per Week	15	19	24	58
Daily	4	3	3	10
Height
Units: cm
arithmetic mean (standard deviation)	168.2 ( 9.17 )	169.7 ( 9.14 )	169 ( 9.43 )	-
Weight
Units: kg
arithmetic mean (standard deviation)	81.84 ( 22.068 )	81.68 ( 20.965 )	80.96 ( 20.316 )	-
Body Mass Index (BMI)
Units: kg/m^2
arithmetic mean (standard deviation)	28.86 ( 7.334 )	28.39 ( 7.312 )	28.27 ( 6.354 )	-

End points

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Reporting group title

Vortioxetine (Lu AA21004)

Reporting 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.

Reporting group title

Duloxetine

Reporting group description

Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.

Reporting group title

Placebo

Reporting group description

Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).

Primary: Change From Baseline to Week 8 in the Digit Symbol Substitution Test (DSST)

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End point title

Change From Baseline to Week 8 in the Digit Symbol Substitution Test (DSST)

End point 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.

End point type

Primary

End point timeframe

Baseline and Week 8

End point values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Number of subjects analysed	175	187	167
Units: Correct symbols
least squares mean (standard error)	4.6 ( 0.53 )	4.06 ( 0.511 )	2.85 ( 0.542 )

Statistical Analysis 1

Comparison groups

Vortioxetine (Lu AA21004) v Placebo

Number of subjects included in analysis

342

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.019 ^[1]

Method

ANCOVA

Parameter type

LS Mean difference

Point estimate

1.75

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

3.21

Variability estimate

Standard error of the mean

Dispersion value

0.744

Notes
[1] - P-value was from an ANCOVA model with treatment and center as fixed factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Duloxetine

Number of subjects included in analysis

354

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.099 ^[2]

Method

ANCOVA

Parameter type

LS Mean difference

Point estimate

1.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.23

upper limit

2.65

Variability estimate

Standard error of the mean

Dispersion value

0.733

Notes
[2] - P-value was from an ANCOVA model with treatment and center as fixed factors and the baseline value as a covariate.

Statistical Analysis 3

Comparison groups

Duloxetine v Vortioxetine (Lu AA21004)

Number of subjects included in analysis

362

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.46 ^[3]

Method

ANCOVA

Parameter type

LS Mean difference

Point estimate

0.54

Confidence interval

level

95%

sides

2-sided

lower limit

-0.89

upper limit

1.96

Variability estimate

Standard error of the mean

Dispersion value

0.725

Notes
[3] - P-value was from an ANCOVA model with treatment and center as fixed factors and the baseline value as a covariate.

Secondary: Change From Baseline to Week 8 in the Perceived Deficits Questionnaire (PDQ) Attention/Concentration and Planning/Organization Subscore

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End point title

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

End point 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 combined. 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.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Number of subjects analysed	169	179	160
Units: score on a scale
least squares mean (standard error)	-8.9 ( 0.55 )	-9.3 ( 0.53 )	-6.3 ( 0.57 )

Statistical Analysis 1

Comparison groups

Vortioxetine (Lu AA21004) v Placebo

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[4]

Method

Mixed models analysis

Parameter type

LS Mean difference

Point estimate

-2.6

Confidence interval

level

95%

sides

2-sided

lower limit

-4.1

upper limit

-1

Variability estimate

Standard error of the mean

Dispersion value

0.78

Notes
[4] - P-value was from a MMRM model with baseline*week, center, week, treatment and week*treatment as factors in the analysis.

Statistical Analysis 2

Comparison groups

Placebo v Duloxetine

Number of subjects included in analysis

339

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[5]

Method

Mixed models analysis

Parameter type

LS Mean difference

Point estimate

-3

Confidence interval

level

95%

sides

2-sided

lower limit

-4.5

upper limit

-1.5

Variability estimate

Standard error of the mean

Dispersion value

0.77

Notes
[5] - P-value was from a MMRM model with baseline*week, center, week, treatment and week*treatment as factors in the analysis.

Secondary: Clinical Global Impressions-Improvement (CGI-I) Score at Week 8

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End point title

Clinical Global Impressions-Improvement (CGI-I) Score at Week 8

End point 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.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Number of subjects analysed	169	179	161
Units: score on a scale
least squares mean (standard error)	2.349 ( 0.0852 )	2.235 ( 0.0826 )	2.639 ( 0.0872 )

Statistical Analysis 1

Comparison groups

Vortioxetine (Lu AA21004) v Placebo

Number of subjects included in analysis

330

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.017 ^[6]

Method

Mixed models analysis

Parameter type

LS Mean difference

Point estimate

-0.29

Confidence interval

level

95%

sides

2-sided

lower limit

-0.528

upper limit

-0.052

Variability estimate

Standard error of the mean

Dispersion value

0.1211

Notes
[6] - P-value was from a MMRM model with baseline*week, center, week, treatment and week*treatment as factors in the analysis.

Statistical Analysis 2

Comparison groups

Placebo v Duloxetine

Number of subjects included in analysis

340

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[7]

Method

Mixed models analysis

Parameter type

LS Mean difference

Point estimate

-0.404

Confidence interval

level

95%

sides

2-sided

lower limit

-0.638

upper limit

-0.169

Variability estimate

Standard error of the mean

Dispersion value

0.1194

Notes
[7] - P-value was from a MMRM model with baseline*week, center, week, treatment and week*treatment as factors in the analysis.

Secondary: Change From Baseline to Week 8 in the Trail Making Test (TMT-A)

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End point title

Change From Baseline to Week 8 in the Trail Making Test (TMT-A)

End point 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.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Number of subjects analysed	173	180	162
Units: seconds
least squares mean (standard error)	-7.7 ( 0.98 )	-8.06 ( 0.955 )	-6.65 ( 1.009 )

No statistical analyses for this end point

Secondary: Change From Baseline to Week 8 in the Trail Making Test B (TMT-B)

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End point title

Change From Baseline to Week 8 in the Trail Making Test B (TMT-B)

End point 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.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Number of subjects analysed	157	170	157
Units: seconds
least squares mean (standard error)	-18.73 ( 2.096 )	-14.6 ( 2.011 )	-9.06 ( 2.101 )

No statistical analyses for this end point

Secondary: Change in Time From Baseline to Week 8 in the Stroop Test

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End point title

Change in Time From Baseline to Week 8 in the Stroop Test

End point 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.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Number of subjects analysed	175	187	167
Units: seconds
least squares mean (standard error)
Congruent (n=174,187,167)	-3.3 ( 1.086 )	-4.54 ( 1.044 )	-4.37 ( 1.105 )
Incongruent (n=172,186,166)	-8.17 ( 1.56 )	-9.83 ( 1.498 )	-8.11 ( 1.586 )

No statistical analyses for this end point

Secondary: Change From Baseline to Week 8 in the Groton Maze Learning Test (GMLT)

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End point title

Change From Baseline to Week 8 in the Groton Maze Learning Test (GMLT)

End point 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.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Number of subjects analysed	169	179	159
Units: errors
least squares mean (standard error)	-5.43 ( 1.355 )	-5.16 ( 1.314 )	-3.49 ( 1.397 )

No statistical analyses for this end point

Secondary: Change From Baseline to Week 8 in the Detection Task (DT)

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End point title

Change From Baseline to Week 8 in the Detection Task (DT)

End point 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.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Number of subjects analysed	175	182	167
Units: Log10 milliseconds
least squares mean (standard error)	-0.05 ( 0.008 )	-0.039 ( 0.0078 )	-0.033 ( 0.0082 )

No statistical analyses for this end point

Secondary: Change From Baseline to Week 8 in the Identification Task (IT)

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End point title

Change From Baseline to Week 8 in the Identification Task (IT)

End point 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.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Number of subjects analysed	175	182	167
Units: Log10 milliseconds
least squares mean (standard error)	-0.037 ( 0.006 )	-0.03 ( 0.0059 )	-0.024 ( 0.0062 )

No statistical analyses for this end point

Secondary: Change From Baseline to Week 8 in the One-Back Task

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End point title

Change From Baseline to Week 8 in the One-Back Task

End point 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.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Number of subjects analysed	175	182	167
Units: Log10 milliseconds
least squares mean (standard error)	-0.028 ( 0.0062 )	-0.024 ( 0.006 )	-0.022 ( 0.0063 )

No statistical analyses for this end point

Secondary: Proportion of Cognitive Dysfunction Improvement Due to Improvement of Depression

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End point title

Proportion of Cognitive Dysfunction Improvement Due to Improvement of Depression ^[8]

End point 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).

End point type

Secondary

End point timeframe

Baseline and Week 8

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Participants in the Placebo arm were not included in this analysis.

End point values	Vortioxetine (Lu AA21004)	Duloxetine
Number of subjects analysed	175	187
Units: proportion of direct effect
number (not applicable)	75.66	48.69

No statistical analyses for this end point

Secondary: Change From Baseline to Week 8 in the MADRS Total Score

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End point title

Change From Baseline to Week 8 in the MADRS Total Score

End point 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.

End point type

Secondary

End point timeframe

Baseline, Week 1, Week 4 and Week 8

End point values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Number of subjects analysed	175	187	167
Units: score on a scale
arithmetic mean (standard deviation)
Change at Week 1	-3.7 ( 4.8 )	-4.6 ( 5.29 )	-3.4 ( 5.03 )
Change at Week 4	-9.8 ( 6.85 )	-11.6 ( 7.94 )	-8 ( 7.98 )
Change at Week 8	-14.3 ( 8.97 )	-15.5 ( 9.23 )	-12.3 ( 9.64 )

No statistical analyses for this end point

Secondary: Percentage of Participants With MADRS Response at Week 8

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End point title

Percentage of Participants With MADRS Response at Week 8

End point 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.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Number of subjects analysed	175	187	167
Units: percentage of participants
number (not applicable)	50.9	54.5	41.3

No statistical analyses for this end point

Secondary: Percentage of Participants in MADRS Remission at Week 8

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End point title

Percentage of Participants in MADRS Remission at Week 8

End point 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.

End point type

Secondary

End point timeframe

Week 8

End point values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Number of subjects analysed	175	187	167
Units: percentage of participants
number (not applicable)	30.3	33.7	21.6

No statistical analyses for this end point

Secondary: Change From Baseline to Week 8 in the Clinical Global Impressions-Severity (CGI-S) Score

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End point title

Change From Baseline to Week 8 in the Clinical Global Impressions-Severity (CGI-S) Score

End point 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.

End point type

Secondary

End point timeframe

Baseline, Week 1, Week 4 and Week 8

End point values	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Number of subjects analysed	175	187	167
Units: score on a scale
least squares mean (standard error)
Change from Baseline at Week 1 (n=174, 187,167)	-0.289 ( 0.0426 )	-0.353 ( 0.041 )	-0.243 ( 0.0435 )
Change from Baseline at Week 4 (n=173,184,165)	-0.951 ( 0.0678 )	-1.17 ( 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 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

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 additional 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.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.1

Reporting group title

Vortioxetine (Lu AA21004)

Reporting 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.

Reporting group title

Duloxetine

Reporting group description

Duloxetine 60 mg, capsules, orally, for up to 8 weeks. Duloxetine 30 mg, capsule, orally, once daily for 1 week taper-down period.

Reporting group title

Placebo

Reporting group description

Placebo matching capsules, orally, once daily for up to 9 weeks (includes 1 week taper down period).

Serious adverse events	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 196 (0.51%)	1 / 207 (0.48%)	2 / 191 (1.05%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Injury, poisoning and procedural complications
Craniocerebral injury
subjects affected / exposed	0 / 196 (0.00%)	1 / 207 (0.48%)	0 / 191 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 196 (0.00%)	1 / 207 (0.48%)	0 / 191 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 196 (0.00%)	0 / 207 (0.00%)	1 / 191 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 196 (0.00%)	0 / 207 (0.00%)	1 / 191 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	1 / 196 (0.51%)	0 / 207 (0.00%)	0 / 191 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Vortioxetine (Lu AA21004)	Duloxetine	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	73 / 196 (37.24%)	84 / 207 (40.58%)	41 / 191 (21.47%)
Nervous system disorders
Dizziness
subjects affected / exposed	6 / 196 (3.06%)	11 / 207 (5.31%)	5 / 191 (2.62%)
occurrences all number	6	11	5
Headache
subjects affected / exposed	20 / 196 (10.20%)	24 / 207 (11.59%)	16 / 191 (8.38%)
occurrences all number	22	25	20
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	11 / 196 (5.61%)	6 / 207 (2.90%)	5 / 191 (2.62%)
occurrences all number	13	6	5
Dry mouth
subjects affected / exposed	6 / 196 (3.06%)	16 / 207 (7.73%)	9 / 191 (4.71%)
occurrences all number	6	17	9
Nausea
subjects affected / exposed	40 / 196 (20.41%)	43 / 207 (20.77%)	8 / 191 (4.19%)
occurrences all number	41	48	8
Infections and infestations
Nasopharyngitis
subjects affected / exposed	7 / 196 (3.57%)	8 / 207 (3.86%)	11 / 191 (5.76%)
occurrences all number	7	8	11
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 196 (1.53%)	12 / 207 (5.80%)	1 / 191 (0.52%)
occurrences all number	3	12	1

More information

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Were there any global substantial amendments to the protocol? Yes

14 Feb 2012

The primary purposes Amendment 1 were to change the dose for duloxetine titration during Week 1, add the CPFQ to the cognitive tests, and add a safety phone call at the end of Week 6.

05 Nov 2012

The primary purposes of amendment 2 were to remove hemoglobin A1C and alcohol exclusion requirements, clarify the exclusion criterion for subclinical hypothyroidism, andupdate unstable medical conditions in the exclusion criteria.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: 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)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline to Week 8 in the Digit Symbol Substitution Test (DSST)

Primary: Change From Baseline to Week 8 in the Digit Symbol Substitution Test (DSST)

Secondary: Change From Baseline to Week 8 in the Perceived Deficits Questionnaire (PDQ) Attention/Concentration and Planning/Organization Subscore

Secondary: Change From Baseline to Week 8 in the Perceived Deficits Questionnaire (PDQ) Attention/Concentration and Planning/Organization Subscore

Secondary: Clinical Global Impressions-Improvement (CGI-I) Score at Week 8

Secondary: Clinical Global Impressions-Improvement (CGI-I) Score at Week 8

Secondary: Change From Baseline to Week 8 in the Trail Making Test (TMT-A)

Secondary: Change From Baseline to Week 8 in the Trail Making Test (TMT-A)

Secondary: Change From Baseline to Week 8 in the Trail Making Test B (TMT-B)

Secondary: Change From Baseline to Week 8 in the Trail Making Test B (TMT-B)

Secondary: Change in Time From Baseline to Week 8 in the Stroop Test

Secondary: Change in Time From Baseline to Week 8 in the Stroop Test

Secondary: Change From Baseline to Week 8 in the Groton Maze Learning Test (GMLT)

Secondary: Change From Baseline to Week 8 in the Groton Maze Learning Test (GMLT)

Secondary: Change From Baseline to Week 8 in the Detection Task (DT)

Secondary: Change From Baseline to Week 8 in the Detection Task (DT)

Secondary: Change From Baseline to Week 8 in the Identification Task (IT)

Secondary: Change From Baseline to Week 8 in the Identification Task (IT)

Secondary: Change From Baseline to Week 8 in the One-Back Task

Secondary: Change From Baseline to Week 8 in the One-Back Task

Secondary: Proportion of Cognitive Dysfunction Improvement Due to Improvement of Depression

Secondary: Proportion of Cognitive Dysfunction Improvement Due to Improvement of Depression

Secondary: Change From Baseline to Week 8 in the MADRS Total Score

Secondary: Change From Baseline to Week 8 in the MADRS Total Score

Secondary: Percentage of Participants With MADRS Response at Week 8

Secondary: Percentage of Participants With MADRS Response at Week 8

Secondary: Percentage of Participants in MADRS Remission at Week 8

Secondary: Percentage of Participants in MADRS Remission at Week 8

Secondary: Change From Baseline to Week 8 in the Clinical Global Impressions-Severity (CGI-S) Score

Secondary: Change From Baseline to Week 8 in the Clinical Global Impressions-Severity (CGI-S) Score

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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)