Effect of Vortioxetine, Paroxetine, and Placebo on Sexual Functioning in Healthy Volunteers

Sponsor

Takeda (Industry)

Overall Status

Completed

CT.gov ID

NCT02932904

Collaborator

(none)

361

Enrollment

Locations

Arms

6.6

Actual Duration (Months)

24.1

Patients Per Site

3.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effect of vortioxetine (10 and 20 mg, once daily) versus paroxetine (20 mg, once daily) on sexual functioning in healthy participants after 5 weeks of double-blind treatment.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: Vortioxetine Drug: Paroxetine Drug: Placebo	Phase 4

Detailed Description

The drug being tested in this study is called vortioxetine. This study will look at the effect of treatment on sexual functioning in healthy participants.

The study will enroll approximately 352 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the four treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

Vortioxetine 10 mg
Vortioxetine 20 mg
Paroxetine 20 mg
Placebo (dummy inactive pill) - this is a capsule that looks like the study drug but has no active ingredient

All participants will be asked to take one tablet/capsule, daily, orally for up to 5 weeks.

This multicenter trial will be conducted in United States. The overall time to participate in this study is approximately 7 weeks. Participants will be contacted by telephone 2 weeks after last dose of study drug for a follow-up assessment.

Study Design

Study Type:

Interventional

Actual Enrollment :

361 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- and Active-Controlled, Phase 4 Study Evaluating the Effect of Vortioxetine 10 and 20 mg/Day vs Paroxetine 20 mg/Day on Sexual Functioning in Healthy Subjects

Actual Study Start Date :

Nov 21, 2016

Actual Primary Completion Date :

May 31, 2017

Actual Study Completion Date :

Jun 9, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vortioxetine 10 mg Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Drug: Vortioxetine Vortioxetine Overencapsulated Tablet
Experimental: Vortioxetine 20 mg Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 1 week followed by vortioxetine 20 mg, overencapsulated tablets, orally, once daily from Week 2, up to 4 weeks.	Drug: Vortioxetine Vortioxetine Overencapsulated Tablet
Active Comparator: Paroxetine 20 mg Paroxetine 20 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Drug: Paroxetine Paroxetine Overencapsulated Tablets.
Placebo Comparator: Placebo Vortioxetine placebo matching-capsules, orally, once daily for up to 5 weeks.	Drug: Placebo Vortioxetine Placebo-matching Capsules.

Outcome Measures

Primary Outcome Measures

Change From Baseline in the Changes in Sexual Functioning Questionnaire (CSFQ-14) Total Score Difference for Vortioxetine Versus Paroxetine at Week 5 in Full Analysis Set (FAS) [Baseline and Week 5]
The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning as a total score (14 items) and on the subscales of pleasure (1 item), desire/frequency (2 items), desire/interest (3 items), arousal (3 items), orgasm (3 items) and 2 additional items are included in the total score, but do not map to a specific phase of the sexual response cycle, rated on a 5-point scale from 1 to 5 with a total score range from 14 to 70. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.
Change From Baseline in the CSFQ-14 Total Score Difference for Vortioxetine Versus Paroxetine at Week 5 in Modified Full Analysis Set 1 (mFAS1) [Baseline and Week 5]
The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning as a total score (14 items) and on the subscales of pleasure (1 item), desire/frequency (2 items), desire/interest (3 items), arousal (3 items), orgasm (3 items) and 2 additional items are included in the total score, but do not map to a specific phase of the sexual response cycle, rated on a 5-point scale from 1 to 5 with a total score range from 14 to 70. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.
Change From Baseline in the CSFQ-14 Total Score Difference for Vortioxetine Versus Paroxetine at Week 5 in Modified Full Analysis Set 2 (mFAS2) [Baseline and Week 5]
The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning as a total score (14 items) and on the subscales of pleasure (1 item), desire/frequency (2 items), desire/interest (3 items), arousal (3 items), orgasm (3 items) and 2 additional items are included in the total score, but do not map to a specific phase of the sexual response cycle, rated on a 5-point scale from 1 to 5 with a total score range from 14 to 70. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.

Secondary Outcome Measures

Change From Baseline in the CSFQ-14 Total Score Difference for Vortioxetine Versus Paroxetine at Weeks 1, 2, 3 and 4 [Baseline and Weeks 1, 2, 3 and 4]
The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning as a total score (14 items) and on the subscales of pleasure (1 item), desire/frequency (2 items), desire/interest (3 items), arousal (3 items), orgasm (3 items) and 2 additional items are included in the total score, but do not map to a specific phase of the sexual response cycle, rated on a 5-point scale from 1 to 5 with a total score range from 14 to 70. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.
Change From Baseline in CSFQ-14 Total Score Difference for Paroxetine Versus Placebo at Weeks 1, 2, 3, 4 and 5 [Baseline and Weeks 1, 2, 3, 4 and 5]
The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning as a total score (14 items) and on the subscales of pleasure (1 item), desire/frequency (2 items), desire/interest (3 items), arousal (3 items), orgasm (3 items) and 2 additional items are included in the total score, but do not map to a specific phase of the sexual response cycle, rated on a 5-point scale from 1 to 5 with a total score range from 14 to 70. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.
Change From Baseline in CSFQ-14 Total Score Difference for Vortioxetine Versus Placebo at Weeks 1, 2, 3, 4 and 5 [Baseline and Weeks 1, 2, 3, 4 and 5]
The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning as a total score (14 items) and on the subscales of pleasure (1 item), desire/frequency (2 items), desire/interest (3 items), arousal (3 items), orgasm (3 items) and 2 additional items are included in the total score, but do not map to a specific phase of the sexual response cycle, rated on a 5-point scale from 1 to 5 with a total score range from 14 to 70. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.
Percentage of Participants Meeting Criteria for Sexual Dysfunction at Weeks 1, 2, 3, 4 and 5 [Weeks 1, 2, 3, 4 and 5]
Sexual dysfunction is defined as CSFQ-14 score ≤47 for men and ≤41 for women.
Change From Baseline in CSFQ-14 Subscales 5 Dimensions at Weeks 1, 2, 3, 4 and 5 [Baseline and Weeks 1, 2, 3, 4 and 5]
The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning on the subscales of pleasure (1 item, score range 1-5), desire/frequency (2 items, score range 2-10), desire/interest (3 items, score range 3-15), arousal (3 items, score range 3-15), and orgasm (3 items, score range 3-15), rated on a 5-point scale from 1 to 5. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.
Change From Baseline in CSFQ-14 3 Phases of the Sexual Response Cycle (Desire, Arousal, and Orgasm/Completion) at Weeks 1, 2, 3, 4 and 5 [Baseline and Weeks 1, 2, 3, 4 and 5]
The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning on the 3 phases of the sexual response cycle , desire (5 items, score range 5-25), arousal (3 items, score range 3-15), and orgasm (3 items, score range 3-15), rated on a 5-point scale from 1 to 5. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Is sexually active and has been in a steady relationship and plans to remain in that relationship for the duration of the study.
Has a body mass index (BMI) of 18 to 35 kg/m^2, inclusive, at the Screening and Baseline Visits.
If female, has a regular menstrual cycle.
Has normal sexual functioning, as defined by a Changes in Sexual Functioning Questionnaire (CSFQ-14) total score >47 (men) or >41 (women) at the Screening and Baseline Visits.
If females, taking allowed hormonal contraceptives is on a stable dose for ≥3 months prior to the Baseline Visit and continues on the stable dose for the duration of the study.

Exclusion Criteria:

Has received vortioxetine and/or paroxetine in a previous clinical study or as a therapeutic agent.
Is positive for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) antibodies, or human immunodeficiency virus (HIV) at the Screening Visit or has any known sexually transmitted diseases.
Has glycosylated hemoglobin (HbA1c) ≥7% at the Screening Visit.
Has a clinically significant abnormal electrocardiogram (ECG) at the Screening Visit.
Has a known history of or currently has increased intraocular pressure or is at risk of acute narrow-angle glaucoma.
Has a history of depression or any other psychiatric illness.
Has a significant risk of suicide according to the investigator's clinical judgment, or has made a suicide attempt in the previous 6 months.
Has current sexual dysfunction, or a history of a diagnosis or treatment of sexual dysfunction.
Has had a surgical or medical procedure on reproductive/genitourinary organs (excluding uncomplicated vasectomy and tubal ligation).
If female, has polycystic ovarian syndrome.
Has hypogonadism or has a free testosterone value outside the normal range at the Screening Visit that is indicative of hypogonadism.
Has a thyroid-stimulating hormone (TSH) value outside the normal range at the Screening Visit that is deemed clinically significant by the investigator.

Contacts and Locations

Locations

	City	State	Country
1	Encino	California	United States
2	Long Beach	California	United States
3	Torrance	California	United States
4	Jacksonville	Florida	United States
5	Orlando	Florida	United States
6	Atlanta	Georgia	United States
7	Decatur	Georgia	United States
8	Saint Louis	Missouri	United States
9	Las Vegas	Nevada	United States
10	Portland	Oregon	United States
11	Austin	Texas	United States
12	Dallas	Texas	United States
13	San Antonio	Texas	United States
14	Charlottesville	Virginia	United States
15	Seattle	Washington	United States

Sponsors and Collaborators

Takeda

Investigators

Study Director: Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

More Information

Publications

None provided.

Responsible Party:

Takeda

ClinicalTrials.gov Identifier:

NCT02932904

Other Study ID Numbers:

Vortioxetine-4001
U1111-1174-1779

First Posted:

Oct 13, 2016

Last Update Posted:

Sep 14, 2018

Last Verified:

Aug 1, 2018

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Takeda

Drug therapy

Additional relevant MeSH terms:

Vortioxetine

Paroxetine

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 16 investigative sites in the United States from 21 November 2016 to 09 June 2017.
Pre-assignment Detail	Healthy volunteers were randomized in a 1:1:1:1 ratio to one of 4 treatment arms: vortioxetine 10 mg, vortioxetine 20 mg, paroxetine or placebo.

Arm/Group Title	Placebo	Paroxetine 20 mg	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Vortioxetine placebo matching-capsules, orally, once daily for up to 5 weeks.	Paroxetine 20 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 1 week followed by vortioxetine 20 mg, overencapsulated tablets, orally, once daily from Week 2, up to 4 weeks.
Period Title: Overall Study
STARTED	92	85	91	93
Treated	91	84	91	91
COMPLETED	76	67	68	79
NOT COMPLETED	16	18	23	14

Baseline Characteristics

Arm/Group Title	Placebo	Paroxetine 20 mg	Vortioxetine 10 mg	Vortioxetine 20 mg	Total
Arm/Group Description	Vortioxetine placebo matching-capsules, orally, once daily for up to 5 weeks.	Paroxetine 20 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 1 week followed by vortioxetine 20 mg, overencapsulated tablets, orally, once daily from Week 2, up to 4 weeks.	Total of all reporting groups
Overall Participants	92	85	91	93	361
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.8 (5.45)	28.9 (5.96)	28.1 (5.56)	28.8 (5.91)	28.4 (5.72)
Sex: Female, Male (Count of Participants)
Female	46 50%	42 49.4%	44 48.4%	44 47.3%	176 48.8%
Male	46 50%	43 50.6%	47 51.6%	49 52.7%	185 51.2%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	21 22.8%	20 23.5%	25 27.5%	18 19.4%	84 23.3%
Non-Hispanic and Latino	71 77.2%	65 76.5%	66 72.5%	75 80.6%	277 76.7%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	3 3.3%	0 0%	3 0.8%
Asian	7 7.6%	3 3.5%	2 2.2%	3 3.2%	15 4.2%
Black or African American	30 32.6%	29 34.1%	31 34.1%	34 36.6%	124 34.3%
Native Hawaiian or Other Pacific Islander	0 0%	1 1.2%	0 0%	0 0%	1 0.3%
White	51 55.4%	49 57.6%	52 57.1%	55 59.1%	207 57.3%
Multiracial	4 4.3%	3 3.5%	3 3.3%	1 1.1%	11 3%
Region of Enrollment (Count of Participants)
United States	92 100%	85 100%	91 100%	93 100%	361 100%
Median Age Categories (Count of Participants)
≤ 28 Years	51 55.4%	43 50.6%	52 57.1%	47 50.5%	193 53.5%
> 28 Years	41 44.6%	42 49.4%	39 42.9%	46 49.5%	168 46.5%
Race Categories (Count of Participants)
White	51 55.4%	49 57.6%	52 57.1%	55 59.1%	207 57.3%
Non-white	41 44.6%	36 42.4%	39 42.9%	38 40.9%	154 42.7%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	172.0 (10.75)	172.1 (10.59)	171.3 (9.14)	170.8 (10.04)	171.5 (10.12)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	76.49 (15.523)	80.19 (16.808)	78.67 (14.850)	75.12 (13.282)	77.56 (15.192)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25.72 (3.925)	26.91 (4.245)	26.77 (4.306)	25.70 (3.668)	26.26 (4.062)
Smoking Classification (Count of Participants)
Participant has never smoked	73 79.3%	70 82.4%	70 76.9%	77 82.8%	290 80.3%
Participant is a current smoker	7 7.6%	2 2.4%	4 4.4%	7 7.5%	20 5.5%
Participant is an ex-smoker	12 13%	13 15.3%	17 18.7%	9 9.7%	51 14.1%
Female Reproductive Status (Count of Participants)
Surgically sterile	3 3.3%	4 4.7%	2 2.2%	3 3.2%	12 3.3%
Female of childbearing potential	43 46.7%	38 44.7%	42 46.2%	41 44.1%	164 45.4%
NA/Participant is male	46 50%	43 50.6%	47 51.6%	49 52.7%	185 51.2%
Duration of Menstruation (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	4.9 (1.36)	4.4 (1.27)	4.2 (1.27)	4.6 (1.37)	4.5 (1.33)
Duration of Menstrual Cycle (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	28.9 (5.35)	28.3 (2.56)	28.2 (7.07)	28.0 (6.94)	28.4 (5.75)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Changes in Sexual Functioning Questionnaire (CSFQ-14) Total Score Difference for Vortioxetine Versus Paroxetine at Week 5 in Full Analysis Set (FAS)
Description	The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning as a total score (14 items) and on the subscales of pleasure (1 item), desire/frequency (2 items), desire/interest (3 items), arousal (3 items), orgasm (3 items) and 2 additional items are included in the total score, but do not map to a specific phase of the sexual response cycle, rated on a 5-point scale from 1 to 5 with a total score range from 14 to 70. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.
Time Frame	Baseline and Week 5

Outcome Measure Data

Analysis Population Description
FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline value for assessment of primary endpoint.

Arm/Group Title	Paroxetine 20 mg	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Paroxetine 20 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 1 week followed by vortioxetine 20 mg, overencapsulated tablets, orally, once daily from Week 2, up to 4 weeks.
Measure Participants	83	85	91
Baseline	59.27 (0.584)	58.56 (0.578)	59.43 (0.560)
Change from Baseline at Week 5	-3.56 (0.758)	-0.82 (0.752)	-2.51 (0.727)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	ANCOVA with last observation carried forward (LOCF) model was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.009
	Comments	The comparisons were between each vortioxetine dose (10 or 20 mg) and paroxetine, and the Holm-Bonferroni method was used to adjust for multiplicity and control the familywise type I error rate at a significance level of 0.05.
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	Least square (LS) Mean Difference
	Estimated Value	2.74
	Confidence Interval	(2-Sided) 95% 0.69 to 4.78
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.040
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.303
	Comments	The comparisons were between each vortioxetine dose (10 or 20 mg) and paroxetine, and the Holm-Bonferroni method was used to adjust for multiplicity and control the familywise type I error rate at a significance level of 0.05.
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95% -0.95 to 3.05
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.017
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in the CSFQ-14 Total Score Difference for Vortioxetine Versus Paroxetine at Weeks 1, 2, 3 and 4
Description	The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning as a total score (14 items) and on the subscales of pleasure (1 item), desire/frequency (2 items), desire/interest (3 items), arousal (3 items), orgasm (3 items) and 2 additional items are included in the total score, but do not map to a specific phase of the sexual response cycle, rated on a 5-point scale from 1 to 5 with a total score range from 14 to 70. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.
Time Frame	Baseline and Weeks 1, 2, 3 and 4

Outcome Measure Data

Analysis Population Description
FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline value for assessment of primary endpoint. Here, number analyzed are the participants who were evaluated for this outcome measure in the FAS.

Arm/Group Title	Paroxetine 20 mg	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Paroxetine 20 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 1 week followed by vortioxetine 20 mg, overencapsulated tablets, orally, once daily from Week 2, up to 4 weeks.
Measure Participants	83	85	91
Week 1	-1.67 (0.457)	-0.54 (0.453)	-0.38 (0.436)
Week 2	-2.40 (0.617)	-1.18 (0.612)	-1.55 (0.592)
Week 3	-2.77 (0.661)	-0.77 (0.655)	-2.36 (0.633)
Week 4	-3.11 (0.688)	-1.20 (0.683)	-2.43 (0.659)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 1, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.072
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95% -0.10 to 2.37
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.627
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 1, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.035
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95% 0.09 to 2.50
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.612
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 2, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.149
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 95% -0.44 to 2.89
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.846
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 2, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.303
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95% -0.78 to 2.48
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.828
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 3, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.028
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.00
	Confidence Interval	(2-Sided) 95% 0.22 to 3.78
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.906
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 3, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.645
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.41
	Confidence Interval	(2-Sided) 95% -1.33 to 2.15
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.886
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 4, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.043
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.91
	Confidence Interval	(2-Sided) 95% 0.06 to 3.77
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.943
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 4, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.465
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95% -1.14 to 2.49
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.923
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in CSFQ-14 Total Score Difference for Paroxetine Versus Placebo at Weeks 1, 2, 3, 4 and 5
Description	The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning as a total score (14 items) and on the subscales of pleasure (1 item), desire/frequency (2 items), desire/interest (3 items), arousal (3 items), orgasm (3 items) and 2 additional items are included in the total score, but do not map to a specific phase of the sexual response cycle, rated on a 5-point scale from 1 to 5 with a total score range from 14 to 70. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.
Time Frame	Baseline and Weeks 1, 2, 3, 4 and 5

Outcome Measure Data

Analysis Population Description
FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline value for assessment of primary endpoint. Here, number analyzed are the participants who were evaluated for this outcome measure in the FAS.

Arm/Group Title	Placebo	Paroxetine 20 mg
Arm/Group Description	Vortioxetine placebo matching-capsules, orally, once daily for up to 5 weeks.	Paroxetine 20 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.
Measure Participants	89	83
Week 1	-0.05 (0.440)	-1.67 (0.457)
Week 2	-1.11 (0.598)	-2.40 (0.617)
Week 3	-0.91 (0.639)	-2.77 (0.661)
Week 4	-0.62 (0.666)	-3.11 (0.688)
Week 5	-0.79 (0.734)	-3.56 (0.758)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 1, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.63
	Confidence Interval	(2-Sided) 95% -2.84 to -0.41
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.616
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 2, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.123
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.29
	Confidence Interval	(2-Sided) 95% -2.93 to 0.35
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.834
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 3, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.039
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.85
	Confidence Interval	(2-Sided) 95% -3.61 to -0.10
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.892
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 4, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.49
	Confidence Interval	(2-Sided) 95% -4.32 to -0.66
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.929
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 5, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.77
	Confidence Interval	(2-Sided) 95% -4.78 to -0.75
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.024
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in CSFQ-14 Total Score Difference for Vortioxetine Versus Placebo at Weeks 1, 2, 3, 4 and 5
Description	The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning as a total score (14 items) and on the subscales of pleasure (1 item), desire/frequency (2 items), desire/interest (3 items), arousal (3 items), orgasm (3 items) and 2 additional items are included in the total score, but do not map to a specific phase of the sexual response cycle, rated on a 5-point scale from 1 to 5 with a total score range from 14 to 70. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.
Time Frame	Baseline and Weeks 1, 2, 3, 4 and 5

Outcome Measure Data

Analysis Population Description
FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline value for assessment of primary endpoint. Here, number analyzed are the participants who were evaluated for this outcome measure in the FAS.

Arm/Group Title	Placebo	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Vortioxetine placebo matching-capsules, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 1 week followed by vortioxetine 20 mg, overencapsulated tablets, orally, once daily from Week 2, up to 4 weeks.
Measure Participants	89	85	91
Week 1	-0.05 (0.440)	-0.54 (0.453)	-0.38 (0.436)
Week 2	-1.11 (0.598)	-1.18 (0.612)	-1.55 (0.592)
Week 3	-0.91 (0.639)	-0.77 (0.655)	-2.36 (0.633)
Week 4	-0.62 (0.666)	-1.20 (0.683)	-2.43 (0.659)
Week 5	-0.79 (0.734)	-0.82 (0.752)	-2.51 (0.727)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 1, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.419
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95% -1.70 to 0.71
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.612
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 1, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.581
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95% -1.51 to 0.85
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.600
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 2, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.938
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95% -1.69 to 1.56
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.828
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 2, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.592
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95% -2.04 to 1.17
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.814
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 3, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.870
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95% -1.60 to 1.89
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.886
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 3, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.098
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.44
	Confidence Interval	(2-Sided) 95% -3.16 to 0.27
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.871
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 4, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.532
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.58
	Confidence Interval	(2-Sided) 95% -2.39 to 1.24
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.923
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 4, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.046
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.82
	Confidence Interval	(2-Sided) 95% -3.60 to -0.03
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.907
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 5, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.977
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95% -2.03 to 1.97
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.018
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 5, ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.087
	Comments
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.72
	Confidence Interval	(2-Sided) 95% -3.68 to 0.25
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.000
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants Meeting Criteria for Sexual Dysfunction at Weeks 1, 2, 3, 4 and 5
Description	Sexual dysfunction is defined as CSFQ-14 score ≤47 for men and ≤41 for women.
Time Frame	Weeks 1, 2, 3, 4 and 5

Outcome Measure Data

Analysis Population Description
FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline value for assessment of primary endpoint. Missing values were imputed by using LOCF. Here, number analyzed are the participants who were evaluated for this outcome measure.

Arm/Group Title	Placebo	Paroxetine 20 mg	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Vortioxetine placebo matching-capsules, orally, once daily for up to 5 weeks.	Paroxetine 20 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 1 week followed by vortioxetine 20 mg, overencapsulated tablets, orally, once daily from Week 2, up to 4 weeks.
Measure Participants	89	83	85	91
Week 1	2.2 2.4%	2.4 2.8%	1.2 1.3%	1.1 1.2%
Week 2	7.9 8.6%	8.4 9.9%	3.5 3.8%	2.2 2.4%
Week 3	4.5 4.9%	8.4 9.9%	3.5 3.8%	6.6 7.1%
Week 4	4.5 4.9%	9.6 11.3%	4.7 5.2%	7.7 8.3%
Week 5	3.4 3.7%	9.6 11.3%	5.9 6.5%	9.9 10.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vortioxetine 10 mg, Vortioxetine 20 mg
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.515
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.44
	Confidence Interval	(2-Sided) 95% 0.037 to 5.201
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Vortioxetine 10 mg, Vortioxetine 20 mg
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.677
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95% 0.049 to 7.051
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.720
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.47
	Confidence Interval	(2-Sided) 95% 0.181 to 11.912
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.732
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95% 0.053 to 7.861
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.913
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95% 0.066 to 11.303
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Vortioxetine 10 mg, Vortioxetine 20 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.164
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.37
	Confidence Interval	(2-Sided) 95% 0.090 to 1.507
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Vortioxetine 10 mg, Vortioxetine 20 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.098
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 95% 0.050 to 1.287
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.758
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95% 0.383 to 3.731
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.256
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.44
	Confidence Interval	(2-Sided) 95% 0.107 to 1.814
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.154
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 95% 0.059 to 1.561
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Vortioxetine 10 mg, Vortioxetine 20 mg
	Comments	Week 3
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.160
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 95% 0.087 to 1.497
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Vortioxetine 10 mg, Vortioxetine 20 mg
	Comments	Week 3
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.744
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95% 0.252 to 2.679
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 3
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.194
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.43
	Confidence Interval	(2-Sided) 95% 0.636 to 9.317
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 3
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.871
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95% 0.181 to 4.261
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 3
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.329
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.00
	Confidence Interval	(2-Sided) 95% 0.497 to 8.037
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Vortioxetine 10 mg, Vortioxetine 20 mg
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.187
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.42
	Confidence Interval	(2-Sided) 95% 0.119 to 1.514
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Vortioxetine 10 mg, Vortioxetine 20 mg
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.729
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95% 0.273 to 2.476
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.133
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.71
	Confidence Interval	(2-Sided) 95% 0.739 to 9.917
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.852
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.15
	Confidence Interval	(2-Sided) 95% 0.266 to 4.961
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.240
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.23
	Confidence Interval	(2-Sided) 95% 0.585 to 8.472
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Vortioxetine 10 mg, Vortioxetine 20 mg
	Comments	Week 5
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using rate of subjects that shifted from normal at baseline to abnormal after baseline as response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.317
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95% 0.166 to 1.789
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Vortioxetine 10 mg, Vortioxetine 20 mg
	Comments	Week 5
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using the rate of subjects that shifted from normal at baseline to abnormal after baseline as the response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.790
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.15
	Confidence Interval	(2-Sided) 95% 0.410 to 3.233
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	Week 5
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using rate of subjects that shifted from normal at baseline to abnormal after baseline as response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.073
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.64
	Confidence Interval	(2-Sided) 95% 0.888 to 14.911
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 5
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using rate of subjects that shifted from normal at baseline to abnormal after baseline as response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.371
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.98
	Confidence Interval	(2-Sided) 95% 0.442 to 8.902
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	Week 5
	Type of Statistical Test	Superiority
	Comments	Odds ratio, 95% confidence intervals and p-values are from logistic regression model using rate of subjects that shifted from normal at baseline to abnormal after baseline as response and explanatory variables for treatment, baseline CSFQ-14 total score, and gender.

Statistical Test of Hypothesis	p-Value	0.046
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.19
	Confidence Interval	(2-Sided) 95% 1.027 to 17.063
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in CSFQ-14 Subscales 5 Dimensions at Weeks 1, 2, 3, 4 and 5
Description	The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning on the subscales of pleasure (1 item, score range 1-5), desire/frequency (2 items, score range 2-10), desire/interest (3 items, score range 3-15), arousal (3 items, score range 3-15), and orgasm (3 items, score range 3-15), rated on a 5-point scale from 1 to 5. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.
Time Frame	Baseline and Weeks 1, 2, 3, 4 and 5

Outcome Measure Data

Analysis Population Description
FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline value for assessment of primary endpoint. Missing values were imputed by using LOCF. Here, number analyzed are the participants who were evaluated for this outcome measure.

Arm/Group Title	Placebo	Paroxetine 20 mg	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Vortioxetine placebo matching-capsules, orally, once daily for up to 5 weeks.	Paroxetine 20 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 1 week followed by vortioxetine 20 mg, overencapsulated tablets, orally, once daily from Week 2, up to 4 weeks.
Measure Participants	89	83	85	91
Pleasure Score: Week 1	-0.07 (0.064)	-0.36 (0.066)	-0.13 (0.065)	-0.15 (0.063)
Pleasure Score: Week 2	-0.26 (0.079)	-0.38 (0.082)	-0.25 (0.081)	-0.26 (0.078)
Pleasure Score: Week 3	-0.23 (0.085)	-0.44 (0.088)	-0.18 (0.087)	-0.42 (0.084)
Pleasure Score: Week 4	-0.18 (0.085)	-0.38 (0.088)	-0.31 (0.087)	-0.37 (0.084)
Pleasure Score: Week 5	-0.21 (0.086)	-0.47 (0.089)	-0.16 (0.088)	-0.33 (0.085)
Desire/Frequency Score: Week 1	-0.03 (0.097)	-0.35 (0.100)	-0.07 (0.099)	-0.23 (0.096)
Desire/Frequency Score: Week 2	-0.30 (0.118)	-0.46 (0.122)	-0.25 (0.120)	-0.46 (0.116)
Desire/Frequency Score: Week 3	-0.33 (0.128)	-0.62 (0.132)	-0.23 (0.131)	-0.50 (0.127)
Desire/Frequency Score: Week 4	-0.25 (0.126)	-0.55 (0.130)	-0.20 (0.129)	-0.43 (0.125)
Desire/Frequency Score: Week 5	-0.28 (0.141)	-0.66 (0.145)	-0.15 (0.144)	-0.49 (0.139)
Desire/Interest Score: Week 1	0.12 (0.162)	-0.15 (0.169)	-0.16 (0.167)	0.09 (0.161)
Desire/Interest Score: Week 2	-0.09 (0.181)	-0.38 (0.186)	-0.11 (0.185)	-0.22 (0.179)
Desire/Interest Score: Week 3	-0.16 (0.193)	-0.47 (0.200)	-0.01 (0.198)	-0.28 (0.191)
Desire/Interest Score: Week 4	-0.11 (0.200)	-0.52 (0.206)	-0.18 (0.204)	-0.35 (0.198)
Desire/Interest Score: Week 5	-0.14 (0.215)	-0.73 (0.223)	-0.05 (0.221)	-0.33 (0.213)
Arousal/Excitement/Erection Score: Week 1	-0.01 (0.136)	-0.30 (0.141)	-0.05 (0.140)	-0.03 (0.135)
Arousal/Excitement/Erection Score: Week 2	-0.34 (0.175)	-0.47 (0.181)	-0.35 (0.179)	-0.30 (0.174)
Arousal/Excitement/Erection Score: Week 3	-0.22 (0.182)	-0.43 (0.188)	-0.08 (0.186)	-0.51 (0.180)
Arousal/Excitement/Erection Score: Week 4	-0.11 (0.181)	-0.54 (0.187)	-0.10 (0.185)	-0.54 (0.179)
Arousal/Excitement/Erection Score: Week 5	-0.19 (0.195)	-0.67 (0.202)	-0.03 (0.200)	-0.54 (0.193)
Orgasm/Completion/Ejaculation Score: Week 1	-0.12 (0.130)	-0.48 (0.135)	-0.22 (0.134)	-0.15 (0.129)
Orgasm/Completion/Ejaculation Score: Week 2	-0.21 (0.158)	-0.61 (0.164)	-0.26 (0.162)	-0.37 (0.157)
Orgasm/Completion/Ejaculation Score: Week 3	-0.20 (0.176)	-0.75 (0.183)	-0.33 (0.180)	-0.67 (0.175)
Orgasm/Completion/Ejaculation Score: Week 4	-0.14 (0.194)	-1.04 (0.201)	-0.45 (0.199)	-0.72 (0.192)
Orgasm/Completion/Ejaculation Score: Week 5	-0.12 (0.206)	-1.09 (0.214)	-0.42 (0.211)	-0.79 (0.204)

7. Secondary Outcome

Title	Change From Baseline in CSFQ-14 3 Phases of the Sexual Response Cycle (Desire, Arousal, and Orgasm/Completion) at Weeks 1, 2, 3, 4 and 5
Description	The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning on the 3 phases of the sexual response cycle , desire (5 items, score range 5-25), arousal (3 items, score range 3-15), and orgasm (3 items, score range 3-15), rated on a 5-point scale from 1 to 5. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.
Time Frame	Baseline and Weeks 1, 2, 3, 4 and 5

Outcome Measure Data

Analysis Population Description
FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid postbaseline value for assessment of primary endpoint. Missing values were imputed by using LOCF. Here, number analyzed are the participants who were evaluated for this outcome measure.

Arm/Group Title	Placebo	Paroxetine 20 mg	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Vortioxetine placebo matching-capsules, orally, once daily for up to 5 weeks.	Paroxetine 20 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 1 week followed by vortioxetine 20 mg, overencapsulated tablets, orally, once daily from Week 2, up to 4 weeks.
Measure Participants	89	83	85	91
Desire Score: Week 1	0.09 (0.225)	-0.50 (0.234)	-0.23 (0.232)	-0.14 (0.223)
Desire Score: Week 2	-0.40 (0.260)	-0.83 (0.269)	-0.34 (0.266)	-0.68 (0.258)
Desire Score: Week 3	-0.50 (0.286)	-1.09 (0.296)	-0.22 (0.293)	-0.77 (0.284)
Desire Score: Week 4	-0.36 (0.297)	-1.07 (0.307)	-0.37 (0.304)	-0.77 (0.294)
Desire Score: Week 5	-0.42 (0.325)	-1.38 (0.336)	-0.19 (0.333)	-0.82 (0.322)
Arousal Score: Week 1	-0.01 (0.136)	-0.30 (0.141)	-0.05 (0.140)	-0.03 (0.135)
Arousal Score: Week 2	-0.34 (0.175)	-0.47 (0.181)	-0.35 (0.179)	-0.30 (0.174)
Arousal Score: Week 3	-0.22 (0.182)	-0.43 (0.188)	-0.08 (0.186)	-0.51 (0.180)
Arousal Score: Week 4	-0.11 (0.181)	-0.54 (0.187)	-0.10 (0.185)	-0.54 (0.179)
Arousal Score: Week 5	-0.19 (0.195)	-0.67 (0.202)	-0.03 (0.200)	-0.54 (0.193)
Orgasm/Completion/Ejaculation Score: Week 1	-0.12 (0.130)	-0.48 (0.135)	-0.22 (0.134)	-0.15 (0.129)
Orgasm/Completion/Ejaculation Score: Week 2	-0.21 (0.158)	-0.61 (0.164)	-0.26 (0.162)	-0.37 (0.157)
Orgasm/Completion/Ejaculation Score: Week 3	-0.20 (0.176)	-0.75 (0.183)	-0.33 (0.180)	-0.67 (0.175)
Orgasm/Completion/Ejaculation Score: Week 4	-0.14 (0.194)	-1.04 (0.201)	-0.45 (0.199)	-0.72 (0.192)
Orgasm/Completion/Ejaculation Score: Week 5	-0.12 (0.206)	-1.09 (0.214)	-0.42 (0.211)	-0.79 (0.204)

8. Primary Outcome

Title	Change From Baseline in the CSFQ-14 Total Score Difference for Vortioxetine Versus Paroxetine at Week 5 in Modified Full Analysis Set 1 (mFAS1)
Description	The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning as a total score (14 items) and on the subscales of pleasure (1 item), desire/frequency (2 items), desire/interest (3 items), arousal (3 items), orgasm (3 items) and 2 additional items are included in the total score, but do not map to a specific phase of the sexual response cycle, rated on a 5-point scale from 1 to 5 with a total score range from 14 to 70. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.
Time Frame	Baseline and Week 5

Outcome Measure Data

Analysis Population Description
mFAS1 included all participants in the FAS except those who had active drug concentrations below the limit of quantification (BLOQ) at all study visits where pharmacokinetic (PK) samples were collected.

Arm/Group Title	Paroxetine 20 mg	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Paroxetine 20 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 1 week followed by vortioxetine 20 mg, overencapsulated tablets, orally, once daily from Week 2, up to 4 weeks.
Measure Participants	74	82	84
Baseline	59.13 (0.614)	58.55 (0.582)	59.36 (0.576)
Change from Baseline at Week 5	-4.01 (0.803)	-0.63 (0.763)	-2.38 (0.754)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.002
	Comments	The comparisons were between each vortioxetine dose (10 or 20 mg) and paroxetine, and the Holm-Bonferroni method was used to adjust for multiplicity and control the familywise type I error rate at a significance level of 0.05.
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	3.38
	Confidence Interval	(2-Sided) 95% 1.25 to 5.51
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.082
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.129
	Comments	The comparisons were between each vortioxetine dose (10 or 20 mg) and paroxetine, and the Holm-Bonferroni method was used to adjust for multiplicity and control the familywise type I error rate at a significance level of 0.05.
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.63
	Confidence Interval	(2-Sided) 95% -0.47 to 3.73
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.068
	Estimation Comments

9. Primary Outcome

Title	Change From Baseline in the CSFQ-14 Total Score Difference for Vortioxetine Versus Paroxetine at Week 5 in Modified Full Analysis Set 2 (mFAS2)
Description	The CSFQ-14 is a structured, self-reported questionnaire designed to measure illness- and medication-related changes in sexual functioning consisting of 14 items that measure sexual functioning as a total score (14 items) and on the subscales of pleasure (1 item), desire/frequency (2 items), desire/interest (3 items), arousal (3 items), orgasm (3 items) and 2 additional items are included in the total score, but do not map to a specific phase of the sexual response cycle, rated on a 5-point scale from 1 to 5 with a total score range from 14 to 70. Higher scores reflect higher sexual functioning. A negative change from baseline indicates that symptoms have worsened.
Time Frame	Baseline and Week 5

Outcome Measure Data

Analysis Population Description
mFAS2 included all participants in the FAS except those who had drug concentrations BLOQ at any study visit where PK samples were collected.

Arm/Group Title	Paroxetine 20 mg	Vortioxetine 10 mg	Vortioxetine 20 mg
Arm/Group Description	Paroxetine 20 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.	Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 1 week followed by vortioxetine 20 mg, overencapsulated tablets, orally, once daily from Week 2, up to 4 weeks.
Measure Participants	60	79	79
Baseline	58.73 (0.675)	58.53 (0.589)	59.23 (0.591)
Change from Baseline at Week 5	-4.78 (0.828)	-0.47 (0.724)	-1.72 (0.724)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 10 mg
	Comments	ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The comparisons were between each vortioxetine dose (10 or 20 mg) and paroxetine, and the Holm-Bonferroni method was used to adjust for multiplicity and control the familywise type I error rate at a significance level of 0.05.
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	4.31
	Confidence Interval	(2-Sided) 95% 2.19 to 6.43
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.078
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paroxetine 20 mg, Vortioxetine 20 mg
	Comments	ANCOVA model with the LOCF method was used for p-value with treatment, pooled center, and gender as fixed factors and with baseline CSFQ-14 total score as a covariate.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.005
	Comments	The comparisons were between each vortioxetine dose (10 or 20 mg) and paroxetine, and the Holm-Bonferroni method was used to adjust for multiplicity and control the familywise type I error rate at a significance level of 0.05.
	Method	ANCOVA with LOCF
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	3.06
	Confidence Interval	(2-Sided) 95% 0.95 to 5.17
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.072
	Estimation Comments

Adverse Events

	Placebo		Paroxetine 20 mg		Vortioxetine 10 mg		Vortioxetine 20 mg
Time Frame	From the first dose of study drug on Day 1 until the Follow-up Contact at Week 7
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		Paroxetine 20 mg		Vortioxetine 10 mg		Vortioxetine 20 mg
Arm/Group Description	Vortioxetine placebo matching-capsules, orally, once daily for up to 5 weeks.		Paroxetine 20 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.		Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 5 weeks.		Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 1 week followed by vortioxetine 20 mg, overencapsulated tablets, orally, once daily from Week 2, up to 4 weeks.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/91 (0%)		0/84 (0%)		0/91 (0%)		0/91 (0%)
Serious Adverse Events
	Placebo		Paroxetine 20 mg		Vortioxetine 10 mg		Vortioxetine 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/91 (0%)		0/84 (0%)		0/91 (0%)		0/91 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Paroxetine 20 mg		Vortioxetine 10 mg		Vortioxetine 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/91 (39.6%)		59/84 (70.2%)		52/91 (57.1%)		40/91 (44%)
Gastrointestinal disorders
Nausea	4/91 (4.4%)		22/84 (26.2%)		26/91 (28.6%)		18/91 (19.8%)
Diarrhoea	3/91 (3.3%)		5/84 (6%)		1/91 (1.1%)		3/91 (3.3%)
General disorders
Fatigue	2/91 (2.2%)		5/84 (6%)		2/91 (2.2%)		3/91 (3.3%)
Infections and infestations
Upper respiratory tract infection	5/91 (5.5%)		3/84 (3.6%)		4/91 (4.4%)		4/91 (4.4%)
Viral upper respiratory tract infection	5/91 (5.5%)		4/84 (4.8%)		1/91 (1.1%)		2/91 (2.2%)
Metabolism and nutrition disorders
Decreased appetite	1/91 (1.1%)		6/84 (7.1%)		4/91 (4.4%)		1/91 (1.1%)
Nervous system disorders
Somnolence	4/91 (4.4%)		10/84 (11.9%)		7/91 (7.7%)		7/91 (7.7%)
Headache	6/91 (6.6%)		6/84 (7.1%)		2/91 (2.2%)		6/91 (6.6%)
Dizziness	1/91 (1.1%)		6/84 (7.1%)		0/91 (0%)		1/91 (1.1%)
Psychiatric disorders
Libido decreased	11/91 (12.1%)		18/84 (21.4%)		14/91 (15.4%)		10/91 (11%)
Orgasm abnormal	2/91 (2.2%)		14/84 (16.7%)		7/91 (7.7%)		3/91 (3.3%)
Anxiety	1/91 (1.1%)		6/84 (7.1%)		1/91 (1.1%)		1/91 (1.1%)
Insomnia	0/91 (0%)		6/84 (7.1%)		1/91 (1.1%)		1/91 (1.1%)
Reproductive system and breast disorders
Ejaculation delayed	0/91 (0%)		5/84 (6%)		2/91 (2.2%)		3/91 (3.3%)

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.

Results Point of Contact

Name/Title	Medical Director
Organization	Takeda
Phone	+1-877-825-3327
Email	trialdisclosures@takeda.com

Responsible Party:

Takeda

ClinicalTrials.gov Identifier:

NCT02932904

Other Study ID Numbers:

Vortioxetine-4001
U1111-1174-1779

First Posted:

Oct 13, 2016

Last Update Posted:

Sep 14, 2018

Last Verified:

Aug 1, 2018