Trial Outcomes & Findings for Active Reference (Fluoxetine) Fixed-dose Study of Vortioxetine in Paediatric Patients Aged 12 to 17 Years With Major Depressive Disorder (MDD) (NCT NCT02709746)

NCT ID: NCT02709746

Last Updated: 2020-08-19

Results Overview

The CDRS-R is a clinician-rated scale to measure the severity of depression of children and adolescents. The CDRS-R consists of 17 items: 14 items rate verbal observations, and three items rate nonverbal observations (tempo of language, hypoactivity, and nonverbal expression of depressed affect). Depression symptoms are rated on a 5-point scale from 1 to 5 for the verbal observations, and a 7-point scale from 1 to 7 for the nonverbal observations. The total score ranges from 17 (normal) to 113 (severe depression).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 784 participants
• Primary outcome timeframe: From Randomization to Week 8
• Results posted on: 2020-08-19

Participant Flow

Patients who did not fulfil the randomization criteria for the Double-blind treatment (DBT) Period, were withdrawn from the study after the Single-blind treatment (SBT) period. Patients who fulfilled the randomization criteria for the DBT Period, continued into the DBT Period.

Participant milestones

Measure	Single-blind Treatment, Placebo Placebo, encapsulated, orally	DBT, Vortioxetine 10 mg Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	DBT, Vortioxetine 20 mg Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	DBT, Fluoxetine 20 mg Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	DBT, Placebo Placebo, encapsulated, orally
Phase A (Single-blind Treatment Period) STARTED	784	0	0	0	0
Phase A (Single-blind Treatment Period) COMPLETED	616	0	0	0	0
Phase A (Single-blind Treatment Period) NOT COMPLETED	168	0	0	0	0
Phase B (Double-blind Treatment Period) STARTED	0	147	162	153	154
Phase B (Double-blind Treatment Period) COMPLETED	0	126	140	138	138
Phase B (Double-blind Treatment Period) NOT COMPLETED	0	21	22	15	16

Reasons for withdrawal

Measure	Single-blind Treatment, Placebo Placebo, encapsulated, orally	DBT, Vortioxetine 10 mg Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	DBT, Vortioxetine 20 mg Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	DBT, Fluoxetine 20 mg Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	DBT, Placebo Placebo, encapsulated, orally
Phase A (Single-blind Treatment Period) Protocol Violation	4	0	0	0	0
Phase A (Single-blind Treatment Period) Not sepcified	14	0	0	0	0
Phase A (Single-blind Treatment Period) Non-compliance with study drug	12	0	0	0	0
Phase A (Single-blind Treatment Period) Lack of Efficacy	7	0	0	0	0
Phase A (Single-blind Treatment Period) Adverse Event	2	0	0	0	0
Phase A (Single-blind Treatment Period) Withdrawal by Subject	12	0	0	0	0
Phase A (Single-blind Treatment Period) Enrolled not treated	7	0	0	0	0
Phase A (Single-blind Treatment Period) Lost to Follow-up	7	0	0	0	0
Phase A (Single-blind Treatment Period) Do not fulfill rand criteria for DBT	103	0	0	0	0
Phase B (Double-blind Treatment Period) Protocol Violation	0	1	0	0	2
Phase B (Double-blind Treatment Period) Other	0	6	5	6	7
Phase B (Double-blind Treatment Period) Non-compliance with study drug	0	1	4	1	0
Phase B (Double-blind Treatment Period) Lack of Efficacy	0	3	0	1	2
Phase B (Double-blind Treatment Period) Adverse Event	0	4	8	5	2
Phase B (Double-blind Treatment Period) Withdrawal by Subject	0	2	2	2	1
Phase B (Double-blind Treatment Period) enrolled not treated	0	0	1	0	0
Phase B (Double-blind Treatment Period) Lost to Follow-up	0	4	2	0	2

Baseline Characteristics

Active Reference (Fluoxetine) Fixed-dose Study of Vortioxetine in Paediatric Patients Aged 12 to 17 Years With Major Depressive Disorder (MDD)

Baseline characteristics by cohort

Measure	Single-blind Treatment (SBT), Placebo n=168 Participants Single-blind treatment, Placebo (encapsulated, orally) and Brief Psychosocial Intervention (BPI) for 4 weeks	DBT, Vortioxetine 10 mg n=147 Participants Eligible patients from SBT period (patients with incomplete improvement), will be randomly assigned (1:1:1:1) double-blind treatment in DBT Period, 8 weeks. Vortioxetine 10 mg/day, encapsulated tablets, orally.	DBT, Vortioxetine 20 mg n=162 Participants Eligible patients from SBT period (patients with incomplete improvement), will be randomly assigned (1:1:1:1) double-blind treatment in DBT Period, 8 weeks. Vortioxetine 20 mg/day, encapsulated tablets, orally.	DBT, Fluoxetine 20 mg n=153 Participants Eligible patients from SBT period (patients with incomplete improvement), will be randomly assigned (1:1:1:1) double-blind treatment in DBT Period, 8 weeks. Fluoxetine 20 mg/day, encapsulated tablets, orally.	DBT, Placebo n=154 Participants Eligible patients from SBT period (patients with incomplete improvement), will be randomly assigned (1:1:1:1) double-blind treatment in DBT Period, 8 weeks. Placebo, encapsulated tablets, orally.	Total n=784 Participants Total of all reporting groups
Age, Continuous	14.7 years STANDARD_DEVIATION 1.61 • n=5 Participants	14.8 years STANDARD_DEVIATION 1.66 • n=7 Participants	14.5 years STANDARD_DEVIATION 1.63 • n=5 Participants	14.8 years STANDARD_DEVIATION 1.60 • n=4 Participants	14.6 years STANDARD_DEVIATION 1.60 • n=21 Participants	14.67 years STANDARD_DEVIATION 1.62 • n=10 Participants
Sex: Female, Male Female	111 Participants n=5 Participants	93 Participants n=7 Participants	97 Participants n=5 Participants	103 Participants n=4 Participants	105 Participants n=21 Participants	509 Participants n=10 Participants
Sex: Female, Male Male	57 Participants n=5 Participants	54 Participants n=7 Participants	65 Participants n=5 Participants	50 Participants n=4 Participants	49 Participants n=21 Participants	275 Participants n=10 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants	2 Participants n=4 Participants	4 Participants n=21 Participants	13 Participants n=10 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants
Race (NIH/OMB) Black or African American	37 Participants n=5 Participants	19 Participants n=7 Participants	19 Participants n=5 Participants	20 Participants n=4 Participants	22 Participants n=21 Participants	117 Participants n=10 Participants
Race (NIH/OMB) White	108 Participants n=5 Participants	108 Participants n=7 Participants	110 Participants n=5 Participants	112 Participants n=4 Participants	106 Participants n=21 Participants	544 Participants n=10 Participants
Race (NIH/OMB) More than one race	15 Participants n=5 Participants	17 Participants n=7 Participants	25 Participants n=5 Participants	17 Participants n=4 Participants	21 Participants n=21 Participants	95 Participants n=10 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	2 Participants n=4 Participants	1 Participants n=21 Participants	14 Participants n=10 Participants
CDRS-R total score at Enrolment	61.24 units on a scale STANDARD_DEVIATION 10.00 • n=5 Participants	64.82 units on a scale STANDARD_DEVIATION 9.38 • n=7 Participants	65.29 units on a scale STANDARD_DEVIATION 9.73 • n=5 Participants	64.06 units on a scale STANDARD_DEVIATION 8.65 • n=4 Participants	64.02 units on a scale STANDARD_DEVIATION 8.96 • n=21 Participants	63.85 units on a scale STANDARD_DEVIATION 9.46 • n=10 Participants
CGI-S at Enrolment	4.82 units on a scale STANDARD_DEVIATION 0.68 • n=5 Participants	4.99 units on a scale STANDARD_DEVIATION 0.77 • n=7 Participants	5.00 units on a scale STANDARD_DEVIATION 0.71 • n=5 Participants	4.97 units on a scale STANDARD_DEVIATION 0.68 • n=4 Participants	4.92 units on a scale STANDARD_DEVIATION 0.69 • n=21 Participants	4.94 units on a scale STANDARD_DEVIATION 0.71 • n=10 Participants

PRIMARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period

The CDRS-R is a clinician-rated scale to measure the severity of depression of children and adolescents. The CDRS-R consists of 17 items: 14 items rate verbal observations, and three items rate nonverbal observations (tempo of language, hypoactivity, and nonverbal expression of depressed affect). Depression symptoms are rated on a 5-point scale from 1 to 5 for the verbal observations, and a 7-point scale from 1 to 7 for the nonverbal observations. The total score ranges from 17 (normal) to 113 (severe depression).

Outcome measures

Measure	Vortioxetine 10 mg/Day n=126 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=139 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) n=265 Participants patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in Children Depression Rating Scale - Revised (CDRS-R) Total Score After Treatment	-17.09 units on a scale Standard Error 1.27	-18.94 units on a scale Standard Error 1.22	-21.95 units on a scale Standard Error 1.23	-18.22 units on a scale Standard Error 1.22	-18.01 units on a scale Standard Error 0.98

SECONDARY outcome

Timeframe: At week 2

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The CDRS-R is a clinician-rated scale to measure the severity of depression of children and adolescents. The CDRS-R consists of 17 items: 14 items rate verbal observations, and three items rate nonverbal observations (tempo of language, hypoactivity, and nonverbal expression of depressed affect). Depression symptoms are rated on a 5-point scale from 1 to 5 for the verbal observations, and a 7-point scale from 1 to 7 for the nonverbal observations. The total score ranges from 17 (normal) to 113 (severe depression).Children and parents answer separately. Rater judges and selects 'Best'.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=145 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=158 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=150 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=153 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in CDRS-R Total Score During Treatment (at Week 2)	-9.58 units on a scale Standard Error 1.02	-10.15 units on a scale Standard Error 0.99	-10.34 units on a scale Standard Error 1.00	-8.83 units on a scale Standard Error 0.98	—

SECONDARY outcome

Timeframe: At week 4

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The CDRS-R is a clinician-rated scale to measure the severity of depression of children and adolescents. The CDRS-R consists of 17 items: 14 items rate verbal observations, and three items rate nonverbal observations (tempo of language, hypoactivity, and nonverbal expression of depressed affect). Depression symptoms are rated on a 5-point scale from 1 to 5 for the verbal observations, and a 7-point scale from 1 to 7 for the nonverbal observations. The total score ranges from 17 (normal) to 113 (severe depression).

Outcome measures

Measure	Vortioxetine 10 mg/Day n=137 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=153 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=145 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=149 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in CDRS-R Total Score During Treatment (at Week 4)	-14.32 units on a scale Standard Error 1.14	-15.03 units on a scale Standard Error 1.10	-16.25 units on a scale Standard Error 1.11	-13.71 units on a scale Standard Error 1.09	—

SECONDARY outcome

Timeframe: At week 6

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The CDRS-R is a clinician-rated scale to measure the severity of depression of children and adolescents. The CDRS-R consists of 17 items: 14 items rate verbal observations, and three items rate nonverbal observations (tempo of language, hypoactivity, and nonverbal expression of depressed affect). Depression symptoms are rated on a 5-point scale from 1 to 5 for the verbal observations, and a 7-point scale from 1 to 7 for the nonverbal observations. The total score ranges from 17 (normal) to 113 (severe depression).

Outcome measures

Measure	Vortioxetine 10 mg/Day n=127 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=145 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=143 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=142 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in CDRS-R Total Score During Treatment (at Week 6)	-15.43 units on a scale Standard Error 1.24	-17.78 units on a scale Standard Error 1.19	-19.20 units on a scale Standard Error 1.2	-16.71 units on a scale Standard Error 1.19	—

SECONDARY outcome

Timeframe: From randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

Change in Children Depression Rating Scale - Revised (CDRS-R) Mood. The CDRS-R has been widely used for the evaluation of children and adolescents with major depressive disorder (MDD). The CDRS-R total score is the sum of the responses to 17 items. Each item is graded on a 5- or 7-point scale. Mood is one of four subscores defined in the CDRS-R: sum of items 8, 11, 14, 15; score range 4 to 28. The highest possible score indicates the most severe measure of depression.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=126 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=139 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in CDRS-R Mood Score	-5.05 units on a scale Standard Error 0.40	-5.47 units on a scale Standard Error 0.38	-6.53 units on a scale Standard Error 0.38	-5.32 units on a scale Standard Error 0.38	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

Change in Children Depression Rating Scale - Revised (CDRS-R): Somatic. The CDRS-R has been widely used for the evaluation of children and adolescents with major depressive disorder (MDD). The CDRS-R total score is the sum of the responses to 17 items. Each item is graded on a 5- or 7-point scale. Somatic is one of four subscores defined in the CDRS-R: sum of items 4, 5, 6, 7, 16, 17; score ranges from 6 to 36. The highest possible score indicates the most severe measure of depression.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=126 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=139 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in CDRS-R Somatic Score	-5.63 units on a scale Standard Error 0.46	-6.03 units on a scale Standard Error 0.44	-6.79 units on a scale Standard Error 0.45	-5.78 units on a scale Standard Error 0.44	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

Change in Children Depression Rating Scale - Revised (CDRS-R): Subjective. The CDRS-R has been widely used for the evaluation of children and adolescents with major depressive disorder (MDD). The CDRS-R total score is the sum of the responses to 17 items. Each item is graded on a 5- or 7-point scale. Subjective is one of four subscores defined in the CDRS-R: sum of items 9, 10, 12, 13; score ranges from 4 to 28. The highest possible score indicates the most severe measure of depression.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=126 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=139 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in CDRS-R Subjective Score	-2.41 units on a scale Standard Error 0.22	-2.63 units on a scale Standard Error 0.21	-3.23 units on a scale Standard Error 0.21	-2.66 units on a scale Standard Error 0.21	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

Change in Children Depression Rating Scale - Revised (CDRS-R): Behaviour. The CDRS-R has been widely used for the evaluation of children and adolescents with major depressive disorder (MDD). The CDRS-R total score is the sum of the responses to 17 items. Each item is graded on a 5- or 7-point scale. behaviour is one of four subscores defined in the CDRS-R:sum of items 1, 2, 3; score ranges from 3 to 21. The highest possible score indicates the most severe measure of depression.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=126 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=139 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in CDRS-R Behaviour Score	-4.32 units on a scale Standard Error 0.38	-4.90 units on a scale Standard Error 0.36	-5.52 units on a scale Standard Error 0.37	-4.73 units on a scale Standard Error 0.36	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

Children Depression Rating Scale - Response: defined as a >= 50% decrease in CDRS-R total score, calculated as (change from baseline [Randomization])/(baseline value - 17).

Outcome measures

Measure	Vortioxetine 10 mg/Day n=126 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=139 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
CDRS-R Response	53 Participants	60 Participants	68 Participants	49 Participants	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

Remission is defined as a CDRS-R total score <= 28.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=126 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=139 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
CDRS-R Remission	21 Participants	24 Participants	32 Participants	20 Participants	—

SECONDARY outcome

Timeframe: From randomization to week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

Using the 10-item depression subscale, assessed by parent (PGBI-10D). Change from randomization to Week 8 in GBI Total Parent/Guardian Version Depression score. GBI is a self-report inventory with 73 items focused on mood-related behaviors including depressive, hypomanic, and biphasic symptoms. One 20-item subscale completed by parent/guardian. Symptoms rated on 4-point Likert scale from 0 (never/hardly ever) to 3 (often/almost constantly). Minimum score 0=better outcome, maximum score 60=worse outcome.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=126 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=139 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in General Behaviour Inventory (GBI) Depression Sub Scale Score Assessed by the Parents	-6.23 units on a scale Standard Deviation 0.56	-6.48 units on a scale Standard Deviation 0.54	-8.00 units on a scale Standard Deviation 0.54	-6.62 units on a scale Standard Deviation 0.53	—

SECONDARY outcome

Timeframe: From randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The GBI 10-item mania scale is a parent- and subject-rated scale designed to screen for manic symptoms in children and adolescents. The 10 items are rated on a scale from 0 (never or hardly ever) to 3 (very often or almost constantly). The total score ranges from 0 to 30 points, with high scores indicating greater pathology.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=126 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=139 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change General Behaviour Inventory (GBI) Depression Subscale Score Assessed by the Child	-5.48 units on a scale Standard Error 0.61	-5.55 units on a scale Standard Error 0.59	-6.30 units on a scale Standard Error 0.59	-6.03 units on a scale Standard Error 0.58	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The PGA is a parent-rated variation of the CGI-I to evaluate the severity of the child's symptoms. The PGA reflects assessments of change from Baseline symptoms using a 7 point scale ranging from 1 (very much improved) to 7 (very much worse).

Outcome measures

Measure	Vortioxetine 10 mg/Day n=125 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=139 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Parent Global Assessment-Global Improvement (PGA) Score	2.80 units on a scale Standard Error 0.10	2.74 units on a scale Standard Error 0.09	2.49 units on a scale Standard Error 0.09	2.72 units on a scale Standard Error 0.09	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The Symbol Digit Modalities Test (SDMT) is a cognitive test designed to assess speed of performance requiring visual perception, spatial decision-making and psychomotor skills. The SDMT consists of 110 geometric symbols that the patient has to substitute with a corresponding digit in a 90-second period. Each correct digit is counted, and the total score ranges from 0 (less than normal functioning) to 110 (greater than normal functioning).

Outcome measures

Measure	Vortioxetine 10 mg/Day n=125 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=140 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=138 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in Symbol Digit Modalities Test (SDMT)	3.75 units on a scale Standard Error 1.02	2.64 units on a scale Standard Error 0.98	2.69 units on a scale Standard Error 0.98	2.41 units on a scale Standard Error 0.97	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The CGI-S provides the clinician's impression of the patient's current state of mental illness. The clinician uses his or her clinical experience of this patient population to rate the severity of the patient's current mental illness on a 7-point scale ranging from 1 (normal - not at all ill) to 7 (among the most extremely ill patients).

Outcome measures

Measure	Vortioxetine 10 mg/Day n=126 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=139 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in Clinical Global Impression Severity of Illness (CGI-S) Score	-1.23 units on a scale Standard Error 0.10	-1.38 units on a scale Standard Error 0.10	-1.59 units on a scale Standard Error 0.10	-1.21 units on a scale Standard Error 0.10	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The CGI-I provides the clinician's impression of the patient's improvement (or worsening). The clinician assesses the patient's condition relative to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). In all cases, the assessment should be made independent of whether the rater believes the improvement is drug-related or not.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=125 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=139 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Clinical Global Impression - Global Improvement (CGI-I) Score	2.81 units on a scale Standard Error 0.10	2.69 units on a scale Standard Error 0.09	2.50 units on a scale Standard Error 0.09	2.73 units on a scale Standard Error 0.09	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

Remission defined as CGI-S score of 1 or 2.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=126 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=139 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
CGI-S Remission	26 Participants	33 Participants	36 Participants	24 Participants	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The Children's Global Assessment Score (CGAS) is a rating scale which measures psychological, social and school functioning for children. The CGAS is a clinician-rated global scale to measure the lowest level of functioning for a child (4 to 16 years) during a specified time period. The CGAS contains behaviourally oriented descriptors at each anchor point that depict behaviours and life situations applicable to a child. The items range in value from 1 (most functionally impaired child) to 100 (the healthiest). A total score above 70 indicates normal function.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=126 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=140 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=138 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in Children's Global Assessment Scale (CGAS) Score	12.24 units on a scale Standard Error 1.25	13.89 units on a scale Standard Error 1.20	16.43 units on a scale Standard Error 1.20	14.52 units on a scale Standard Error 1.19	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue and pain using visual analogue scales. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The patients are asked to mark on the line how they feel. A lower value represents a better outcome.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=124 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=140 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=138 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in Pediatric Quality of Life Inventory (PedsQL) Visual Analogue Scales (VAS): Afraid or Scared (Anxiety) Score	-0.47 units on a scale Standard Error 0.19	-0.76 units on a scale Standard Error 0.18	-0.78 units on a scale Standard Error 0.18	-0.71 units on a scale Standard Error 0.18	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue and pain using visual analogue scales. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The patients are asked to mark on the line how they feel. A lower value represents a better outcome.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=124 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=140 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=138 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in PedsQL VAS: Sad or Blue (Sadness) Score	-1.90 units on a scale Standard Error 0.26	-1.71 units on a scale Standard Error 0.25	-2.45 units on a scale Standard Error 0.25	-2.12 units on a scale Standard Error 0.24	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue and pain using visual analogue scales. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The patients are asked to mark on the line how they feel. A lower value represents a better outcome.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=124 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=140 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=138 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in PedsQL VAS: Angry Score	-0.51 units on a scale Standard Error 0.23	-0.70 units on a scale Standard Error 0.23	-1.01 units on a scale Standard Error 0.23	-0.59 units on a scale Standard Error 0.23	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue and pain using visual analogue scales. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The patients are asked to mark on the line how they feel. A lower value represents a better outcome.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=124 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=140 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=138 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in PedsQL VAS: Worry Score	-0.96 units on a scale Standard Error 0.25	-1.17 units on a scale Standard Error 0.24	-0.91 units on a scale Standard Error 0.24	-1.33 units on a scale Standard Error 0.24	—

SECONDARY outcome

Timeframe: From Randomization to week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue and pain using visual analogue scales. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The patients are asked to mark on the line how they feel. A lower value represents a better outcome.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=124 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=140 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=138 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in PedsQL VAS: Tired (Fatigue) Score	-1.18 units on a scale Standard Error 0.29	-1.40 units on a scale Standard Error 0.28	-1.55 units on a scale Standard Error 0.28	-1.27 units on a scale Standard Error 0.28	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue and pain using visual analogue scales. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The patients are asked to mark on the line how they feel. A lower value represents a better outcome.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=124 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=140 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=138 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in PedsQL VAS: Pain or Hurt Score	-1.12 units on a scale Standard Error 0.22	-0.97 units on a scale Standard Error 0.21	-0.83 units on a scale Standard Error 0.21	-0.76 units on a scale Standard Error 0.21	—

SECONDARY outcome

Timeframe: From Randomization to week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL™ VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue, and pain using visual analogue scales. The functionality for each domain is measured on a 10cm line with a happy face at one end and a sad face at the other (0-10 points). The patients are asked to mark on the line how they feel. The total score is the average of all 6 items. A lower value represents a better outcome.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=124 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=140 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=138 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in PedsQL VAS Total Average Score	-1.00 units on a scale Standard Error 0.17	-1.13 units on a scale Standard Error 0.16	-1.33 units on a scale Standard Error 0.16	-1.14 units on a scale Standard Error 0.16	—

SECONDARY outcome

Timeframe: From Randomization to week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue and pain using visual analogue scales. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The patients are asked to mark on the line how they feel. The average emotional distress summary score is the mean of the anxiety, sadness, anger, and worry items. A lower value represents a better outcome.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=124 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=140 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=138 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in PedsQL Emotional Distress Summary Average Score	-0.93 units on a scale Standard Error 0.18	-1.09 units on a scale Standard Error 0.17	-1.33 units on a scale Standard Error 0.17	-1.18 units on a scale Standard Error 0.17	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

PQ-LES-Q total score (items 1 to 14). The PQ-LES-Q is a patient-rated scale designed to assess satisfaction with life. It is an adaptation of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), which is used to measure quality of life in adults. The PQ LES Q consist of 15 items, item 1-14 assess the degree of satisfaction experienced by subjects in various areas of daily functioning (and item 15 allows subjects to summarize their experience in a global rating). Each item is rated on a 5-point scale from 1 (very poor) to 5 (very good). The total score range of item 1-14 (this outcome measurement) is 14 to 70, with higher scores indicating greater satisfaction.

Outcome measures

Measure	Vortioxetine 10 mg/Day n=125 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=140 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in Paediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) Total Scores	7.62 units on a scale Standard Error 0.97	7.56 units on a scale Standard Error 0.93	9.26 units on a scale Standard Error 0.94	7.06 units on a scale Standard Error 0.92	—

SECONDARY outcome

Timeframe: From Randomization to Week 8

Population: Double-blind treatment period. There where overall numbers of participants analyzed are not consistent with numbers provided in the participant flow can be due to particpant flow module total number of patients also includes patients that were enrolled but not treated and other reasons of discontinuation from the study.

PQ-LES-Q overall evaluation score (item 15). The PQ-LES-Q is a patient-rated scale designed to assess satisfaction with life. It is an adaptation of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), which is used to measure quality of life in adults. The PQ-LES-Q consist of 15 items, item 1-14 assess the degree of satisfaction experienced by subjects in various areas of daily functioning and item 15 allows subjects to summarize their experience in a global rating (this outcome measurement). Item 15 is rated on a 5-point scale from 1 (very poor) to 5 (very good).

Outcome measures

Measure	Vortioxetine 10 mg/Day n=125 Participants Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Vortioxetine 20 mg/Day n=140 Participants Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	Fluoxetine 20 mg/Day, n=137 Participants Fluoxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	Placebo n=137 Participants Placebo: Encapsulated tablet	Vortioxetine Average (Avg. VOR) patients are randomized to one of four treatments. Avg.- VOR is a calculation based on the treatment estimates from VOR 10 mg and VOR 20 mg.
Change in PQ-LES-Q Overall Score	0.54 units on a scale Standard Error 0.08	0.43 units on a scale Standard Error 0.08	0.67 units on a scale Standard Error 0.08	0.51 units on a scale Standard Error 0.08	—

Adverse Events

SBT, Placebo

Serious events: 13 serious events

Other events: 128 other events

Deaths: 0 deaths

DBT, Vortioxetine 10 mg

Serious events: 4 serious events

Other events: 47 other events

Deaths: 0 deaths

DBT, Vortioxetine 20 mg

Serious events: 7 serious events

Other events: 57 other events

Deaths: 0 deaths

DBT, Fluoxetine 20 mg

Serious events: 3 serious events

Other events: 40 other events

Deaths: 0 deaths

DBT, Placebo

Serious events: 1 serious events

Other events: 30 other events

Deaths: 0 deaths

Serious adverse events

Measure	SBT, Placebo n=777 participants at risk Patients not randomized to DBT period	DBT, Vortioxetine 10 mg n=147 participants at risk Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	DBT, Vortioxetine 20 mg n=161 participants at risk Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	DBT, Fluoxetine 20 mg n=153 participants at risk Vortioxetine 20 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	DBT, Placebo n=154 participants at risk Placebo, encapsulated tablet, orally
Infections and infestations Pneumonia bacterial	0.00% 0/777 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/147 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.62% 1/161 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/153 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Infections and infestations Viral upper respiratory tract infection	0.00% 0/777 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/147 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.62% 1/161 • Number of events 3 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/153 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Injury, poisoning and procedural complications Head injury	0.00% 0/777 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/147 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/161 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.65% 1/153 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Psychiatric disorders Depression	0.00% 0/777 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/147 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.62% 1/161 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/153 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Psychiatric disorders Generalised anxiety disorder	0.13% 1/777 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/147 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/161 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/153 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Psychiatric disorders Suicidal behaviour	0.13% 1/777 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/147 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/161 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/153 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Psychiatric disorders Suicidal ideation	0.77% 6/777 • Number of events 6 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.68% 1/147 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	1.9% 3/161 • Number of events 4 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	1.3% 2/153 • Number of events 2 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Psychiatric disorders Suicide attempt	0.26% 2/777 • Number of events 2 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/147 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.62% 1/161 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/153 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Reproductive system and breast disorders Dysmenorrhoea	0.13% 1/777 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/147 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/161 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/153 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Infections and infestations Meningitis	0.00% 0/777 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/147 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.62% 1/161 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/153 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Infections and infestations Influenza	0.13% 1/777 • Number of events 3 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/147 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/161 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/153 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Blood and lymphatic system disorders Lymphadenitis	0.13% 1/777 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/147 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/161 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/153 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Infections and infestations Appendicitis	0.13% 1/777 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.68% 1/147 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/161 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/153 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Infections and infestations Bronchitis viral	0.00% 0/777 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.68% 1/147 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/161 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/153 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Infections and infestations Gastroenteritis	0.00% 0/777 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.68% 1/147 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/161 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/153 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/154 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Infections and infestations Gastrointestinal viral infection	0.00% 0/777 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/147 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/161 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.00% 0/153 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.65% 1/154 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.

Other adverse events

Measure	SBT, Placebo n=777 participants at risk Patients not randomized to DBT period	DBT, Vortioxetine 10 mg n=147 participants at risk Vortioxetine 10 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	DBT, Vortioxetine 20 mg n=161 participants at risk Vortioxetine 20 mg/day: 20 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed	DBT, Fluoxetine 20 mg n=153 participants at risk Vortioxetine 20 mg/day: 10 mg/day, encapsulated tablet (with addition of lower initial dose levels). Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed	DBT, Placebo n=154 participants at risk Placebo, encapsulated tablet, orally
Gastrointestinal disorders Nausea	3.6% 28/777 • Number of events 31 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	14.3% 21/147 • Number of events 23 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	19.3% 31/161 • Number of events 48 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	6.5% 10/153 • Number of events 16 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	4.5% 7/154 • Number of events 9 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Gastrointestinal disorders Diarrhoea	1.7% 13/777 • Number of events 14 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	3.4% 5/147 • Number of events 5 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	5.6% 9/161 • Number of events 10 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	4.6% 7/153 • Number of events 11 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	3.2% 5/154 • Number of events 5 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Gastrointestinal disorders Vomiting	1.7% 13/777 • Number of events 13 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	4.8% 7/147 • Number of events 7 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	9.3% 15/161 • Number of events 20 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	5.2% 8/153 • Number of events 10 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	0.65% 1/154 • Number of events 1 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Infections and infestations Nasopharyngitis	3.3% 26/777 • Number of events 28 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	4.1% 6/147 • Number of events 7 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	6.2% 10/161 • Number of events 11 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	6.5% 10/153 • Number of events 12 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	3.2% 5/154 • Number of events 7 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Nervous system disorders Dizziness	2.7% 21/777 • Number of events 23 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	7.5% 11/147 • Number of events 14 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	4.3% 7/161 • Number of events 7 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	3.9% 6/153 • Number of events 8 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	3.2% 5/154 • Number of events 6 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.
Nervous system disorders Headache	8.4% 65/777 • Number of events 85 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	15.6% 23/147 • Number of events 37 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	12.4% 20/161 • Number of events 46 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	6.5% 10/153 • Number of events 16 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.	7.8% 12/154 • Number of events 19 • 16 weeks There where the total numbers of participants at risk are not onsistent with numbers provided in the particpant flow module is due that patients that were enrolled but not treated are included in the total number in the participant flow module.

Additional Information

Email contact via

H. Lundbeck A/S

Phone: +45 36301311

Email: LundbeckClinicalTrials@Lundbeck.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place