Trial Outcomes & Findings for Active Reference (Fluoxetine) Fixed-dose Study of Vortioxetine in Paediatric Participants Aged 7 to 11 Years With Major Depressive Disorder (MDD) (NCT NCT02709655)

Results Overview

The CDRS-R is a clinician-rated scale to measure the severity of depression in children and adolescents. The CDRS-R was rated by a clinician following interviews with the child and parent and consisted of 17 items out of which 3 items rated nonverbal observations (listless speech, hypoactivity, and depressed affect). Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. A rating of 1 indicated normal functioning and a higher number indicated a greater degree of depression. The total score ranged from 17 (normal) to 113 (severe depression). Least square (LS) mean was estimated using a restricted maximum likelihood (REML)-based Mixed Model Repeated Measurements (MMRM) approach.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

683 participants

Primary outcome timeframe

Baseline (Week 4 of Phase A), Week 8 of Phase B

Results posted on

2022-09-22

Participant Flow

This study included 2 periods: single-blind (SB) (treatment with standardized brief psychosocial intervention \[BPI\] and placebo) and double-blind (DB) (treatment with BPI and placebo, vortioxetine 10 milligrams \[mg\]/day, vortioxetine 20 mg/day, or fluoxetine 20 mg/day).

Participants who demonstrated an incomplete improvement in depressive symptoms at the end of the SB period (Week 4) entered the DB period to receive BPI (2 sessions) and treatment as follows: Prior to the interim analysis, participants were randomized in a 1:1:1:1 ratio to placebo, vortioxetine 10 mg/day, vortioxetine 20 mg/day, or fluoxetine 20 mg/day. After interim analysis, participants were randomized in a 1:1:1 ratio to placebo, vortioxetine 10 mg/day, or vortioxetine 20 mg/day.

Participant milestones

Participant milestones
Measure	Single-Blind: Placebo Participants received BPI (3 sessions) and placebo capsules orally once daily for 4 weeks.	Double-Blind: Placebo Participants received placebo capsules orally once daily for 8 weeks. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 10 mg Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days and thereafter they received 10 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 20 mg Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days, and thereafter they received vortioxetine 20 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Fluoxetine 20 mg Participants initiated treatment with fluoxetine 10 mg/day orally for 6 days and thereafter they received 20 mg/day. for up to Week 8. Based on the tolerability, fluoxetine dose could be reduced by 10 mg/day at Week 4. Participants received 2 sessions of BPI also.
Single-Blind Phase (4 Weeks) STARTED	683	0	0	0	0
Single-Blind Phase (4 Weeks) Received at Least 1 Dose of Study Drug	677	0	0	0	0
Single-Blind Phase (4 Weeks) COMPLETED	540	0	0	0	0
Single-Blind Phase (4 Weeks) NOT COMPLETED	143	0	0	0	0
Double-Blind Phase (8 Weeks) STARTED	0	153	151	153	83
Double-Blind Phase (8 Weeks) Received at Least 1 Dose of Study Drug	0	153	151	153	83
Double-Blind Phase (8 Weeks) Full Analysis Set (FAS)	0	153	148	148	81
Double-Blind Phase (8 Weeks) COMPLETED	0	138	135	133	78
Double-Blind Phase (8 Weeks) NOT COMPLETED	0	15	16	20	5

Reasons for withdrawal

Reasons for withdrawal
Measure	Single-Blind: Placebo Participants received BPI (3 sessions) and placebo capsules orally once daily for 4 weeks.	Double-Blind: Placebo Participants received placebo capsules orally once daily for 8 weeks. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 10 mg Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days and thereafter they received 10 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 20 mg Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days, and thereafter they received vortioxetine 20 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Fluoxetine 20 mg Participants initiated treatment with fluoxetine 10 mg/day orally for 6 days and thereafter they received 20 mg/day. for up to Week 8. Based on the tolerability, fluoxetine dose could be reduced by 10 mg/day at Week 4. Participants received 2 sessions of BPI also.
Single-Blind Phase (4 Weeks) Adverse Event	2	0	0	0	0
Single-Blind Phase (4 Weeks) Lack of Efficacy	8	0	0	0	0
Single-Blind Phase (4 Weeks) Non-compliance with study drug	3	0	0	0	0
Single-Blind Phase (4 Weeks) Protocol Violation	3	0	0	0	0
Single-Blind Phase (4 Weeks) Withdrawal by Subject	15	0	0	0	0
Single-Blind Phase (4 Weeks) Lost to Follow-up	1	0	0	0	0
Single-Blind Phase (4 Weeks) Failure to meet randomization criteria	85	0	0	0	0
Single-Blind Phase (4 Weeks) Other than specified	20	0	0	0	0
Single-Blind Phase (4 Weeks) Enrolled but not treated	6	0	0	0	0
Double-Blind Phase (8 Weeks) Adverse Event	0	1	2	3	0
Double-Blind Phase (8 Weeks) Lack of Efficacy	0	2	0	0	1
Double-Blind Phase (8 Weeks) Non-compliance with study drug	0	1	3	6	1
Double-Blind Phase (8 Weeks) Protocol Violation	0	1	0	0	0
Double-Blind Phase (8 Weeks) Withdrawal by Subject	0	4	4	4	1
Double-Blind Phase (8 Weeks) Lost to Follow-up	0	1	0	2	0
Double-Blind Phase (8 Weeks) Other than specified	0	5	7	5	2

Baseline Characteristics

Baseline measure was taken for all participants randomized to Phase B.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Single-Blind: Placebo n=677 Participants Participants received BPI (3 sessions) and placebo capsules orally once daily for 4 weeks.
Age, Continuous	9.3 years STANDARD_DEVIATION 1.42 • n=677 Participants
Sex: Female, Male Female	312 Participants n=677 Participants
Sex: Female, Male Male	365 Participants n=677 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	1 Participants n=677 Participants
Race/Ethnicity, Customized Race · Asian	2 Participants n=677 Participants
Race/Ethnicity, Customized Race · Black or African American	112 Participants n=677 Participants
Race/Ethnicity, Customized Race · Not Reported	12 Participants n=677 Participants
Race/Ethnicity, Customized Race · Other	229 Participants n=677 Participants
Race/Ethnicity, Customized Race · White	321 Participants n=677 Participants
Children Depression Rating Scale - Revised (CDRS-R) Total Score	63.4 units on a scale STANDARD_DEVIATION 9.12 • n=530 Participants • Baseline measure was taken for all participants randomized to Phase B.

PRIMARY outcome

Timeframe: Baseline (Week 4 of Phase A), Week 8 of Phase B

Population: Full analysis set (FAS) included all participants randomized to the double-blind, 8-week treatment period (Phase B) who took at least 1 dose of double-blind study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure.

The CDRS-R is a clinician-rated scale to measure the severity of depression in children and adolescents. The CDRS-R was rated by a clinician following interviews with the child and parent and consisted of 17 items out of which 3 items rated nonverbal observations (listless speech, hypoactivity, and depressed affect). Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. A rating of 1 indicated normal functioning and a higher number indicated a greater degree of depression. The total score ranged from 17 (normal) to 113 (severe depression). Least square (LS) mean was estimated using a restricted maximum likelihood (REML)-based Mixed Model Repeated Measurements (MMRM) approach.

Outcome measures

Outcome measures
Measure	Double-Blind: Placebo n=136 Participants Participants received placebo capsules orally once daily for 8 weeks. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 10 mg n=132 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days and thereafter they received 10 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 20 mg n=134 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days, and thereafter they received vortioxetine 20 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Fluoxetine 20 mg n=78 Participants Participants initiated treatment with fluoxetine 10 mg/day orally for 6 days and thereafter they received 20 mg/day. for up to Week 8. Based on the tolerability, fluoxetine dose could be reduced by 10 mg/day at Week 4. Participants received 2 sessions of BPI also.	Vortioxetine Average (Avg. VOR) n=266 Participants Avg. VOR is the average dose effect of the 2 vortioxetine doses (Vortioxetine 10 mg and Vortioxetine 20 mg).
Change From Baseline in Children Depression Rating Scale - Revised (CDRS-R) Total Score at Week 8 of Phase B	-17.48 units on a scale Standard Error 1.35	-19.20 units on a scale Standard Error 1.37	-19.94 units on a scale Standard Error 1.37	-20.78 units on a scale Standard Error 1.60	-19.57 units on a scale Standard Error 1.16

SECONDARY outcome

Timeframe: Baseline (Week 4 of Phase A), Weeks 2, 4, and 6 of Phase B

Population: FAS included all participants randomized to the double-blind, 8-week treatment period (Phase B) who took at least 1 dose of double-blind study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. Number analyzed = participants evaluable at specified timepoint.

The CDRS-R is a clinician-rated scale to measure the severity of depression in children and adolescents. The CDRS-R was rated by a clinician following interviews with the child and parent and consisted of 17 items out of which 3 items rated nonverbal observations (listless speech, hypoactivity, and depressed affect). Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. A rating of 1 indicated normal functioning and a higher number indicated a greater degree of depression. The total score ranged from 17 (normal) to 113 (severe depression).

Outcome measures

Outcome measures
Measure	Double-Blind: Placebo n=153 Participants Participants received placebo capsules orally once daily for 8 weeks. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 10 mg n=147 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days and thereafter they received 10 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 20 mg n=146 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days, and thereafter they received vortioxetine 20 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Fluoxetine 20 mg n=80 Participants Participants initiated treatment with fluoxetine 10 mg/day orally for 6 days and thereafter they received 20 mg/day. for up to Week 8. Based on the tolerability, fluoxetine dose could be reduced by 10 mg/day at Week 4. Participants received 2 sessions of BPI also.	Vortioxetine Average (Avg. VOR) Avg. VOR is the average dose effect of the 2 vortioxetine doses (Vortioxetine 10 mg and Vortioxetine 20 mg).
Change From Baseline in CDRS-R Total Score at Weeks 2, 4, and 6 of Phase B Change at Week 4	-13.15 units on a scale Standard Error 1.28	-14.56 units on a scale Standard Error 1.30	-15.62 units on a scale Standard Error 1.30	-13.97 units on a scale Standard Error 1.50	—
Change From Baseline in CDRS-R Total Score at Weeks 2, 4, and 6 of Phase B Change at Week 2	-9.20 units on a scale Standard Error 1.17	-9.54 units on a scale Standard Error 1.18	-10.30 units on a scale Standard Error 1.19	-10.17 units on a scale Standard Error 1.32	—
Change From Baseline in CDRS-R Total Score at Weeks 2, 4, and 6 of Phase B Change at Week 6	-16.00 units on a scale Standard Error 1.32	-17.64 units on a scale Standard Error 1.34	-18.28 units on a scale Standard Error 1.34	-17.75 units on a scale Standard Error 1.56	—

SECONDARY outcome

Timeframe: Baseline (Week 4 of Phase A), Weeks 2, 4, 6, and 8 of Phase B

Population: FAS included all participants randomized to the double-blind, 8-week treatment period (Phase B) who took at least 1 dose of double-blind study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. Number analyzed = participants evaluable for specified categories.

The CDRS-R was rated by a clinician following interviews with the child and parent and consisted of 17 items out of which 3 items rated nonverbal observations (listless speech, hypoactivity, and depressed affect). Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. A rating of 1 indicated normal functioning and a higher number indicated a greater degree of depression. The total score ranged from 17 (normal) to 113 (severe depression). Four subscores were defined based on the CDRS-R: Mood: sum of items 8, 11, 14, 15; score range 4 to 28, Somatic: sum of items 4, 5, 6, 7, 16, 17; score range 6 to 36, Subjective: sum of items 9, 10, 12, 13; score range 4 to 28, and Behaviour: sum of items 1, 2, 3; score range 3 to 21. Higher scores indicated the most severe measure of depression.

Outcome measures

Outcome measures
Measure	Double-Blind: Placebo n=153 Participants Participants received placebo capsules orally once daily for 8 weeks. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 10 mg n=147 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days and thereafter they received 10 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 20 mg n=146 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days, and thereafter they received vortioxetine 20 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Fluoxetine 20 mg n=80 Participants Participants initiated treatment with fluoxetine 10 mg/day orally for 6 days and thereafter they received 20 mg/day. for up to Week 8. Based on the tolerability, fluoxetine dose could be reduced by 10 mg/day at Week 4. Participants received 2 sessions of BPI also.	Vortioxetine Average (Avg. VOR) Avg. VOR is the average dose effect of the 2 vortioxetine doses (Vortioxetine 10 mg and Vortioxetine 20 mg).
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Mood Score: Change at Week 2	-2.82 units on a scale Standard Error 0.40	-3.10 units on a scale Standard Error 0.40	-3.47 units on a scale Standard Error 0.40	-3.02 units on a scale Standard Error 0.45	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Mood Score: Change at Week 4	-3.69 units on a scale Standard Error 0.42	-4.39 units on a scale Standard Error 0.43	-4.77 units on a scale Standard Error 0.43	-3.73 units on a scale Standard Error 0.49	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Mood Score: Change at Week 6	-4.67 units on a scale Standard Error 0.43	-5.39 units on a scale Standard Error 0.44	-5.52 units on a scale Standard Error 0.44	-4.97 units on a scale Standard Error 0.51	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Mood Score: Change at Week 8	-5.08 units on a scale Standard Error 0.44	-5.64 units on a scale Standard Error 0.44	-5.95 units on a scale Standard Error 0.45	-5.84 units on a scale Standard Error 0.51	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Somatic Score: Change at Week 2	-2.81 units on a scale Standard Error 0.44	-2.61 units on a scale Standard Error 0.44	-2.88 units on a scale Standard Error 0.44	-3.02 units on a scale Standard Error 0.50	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Somatic Score: Change at Week 4	-4.08 units on a scale Standard Error 0.47	-4.30 units on a scale Standard Error 0.48	-4.70 units on a scale Standard Error 0.48	-4.26 units on a scale Standard Error 0.56	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Somatic Score: Change at Week 6	-4.86 units on a scale Standard Error 0.48	-5.53 units on a scale Standard Error 0.49	-5.33 units on a scale Standard Error 0.49	-5.57 units on a scale Standard Error 0.57	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Somatic Score: Change at Week 8	-5.38 units on a scale Standard Error 0.49	-6.15 units on a scale Standard Error 0.50	-6.08 units on a scale Standard Error 0.50	-6.44 units on a scale Standard Error 0.57	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Subjective Score: Change at Week 2	-1.44 units on a scale Standard Error 0.22	-1.46 units on a scale Standard Error 0.22	-1.43 units on a scale Standard Error 0.22	-1.56 units on a scale Standard Error 0.25	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Subjective Score: Change at Week 4	-2.04 units on a scale Standard Error 0.23	-2.12 units on a scale Standard Error 0.23	-2.20 units on a scale Standard Error 0.23	-2.17 units on a scale Standard Error 0.27	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Subjective Score: Change at Week 6	-2.43 units on a scale Standard Error 0.24	-2.42 units on a scale Standard Error 0.24	-2.65 units on a scale Standard Error 0.24	-2.38 units on a scale Standard Error 0.28	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Subjective Score: Change at Week 8	-2.56 units on a scale Standard Error 0.24	-2.59 units on a scale Standard Error 0.24	-2.84 units on a scale Standard Error 0.24	-2.65 units on a scale Standard Error 0.28	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Behaviour Score: Change at Week 2	-2.16 units on a scale Standard Error 0.34	-2.40 units on a scale Standard Error 0.34	-2.56 units on a scale Standard Error 0.35	-2.61 units on a scale Standard Error 0.39	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Behaviour Score: Change at Week 4	-3.39 units on a scale Standard Error 0.38	-3.77 units on a scale Standard Error 0.39	-4.00 units on a scale Standard Error 0.39	-3.80 units on a scale Standard Error 0.45	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Behaviour Score: Change at Week 6	-4.09 units on a scale Standard Error 0.39	-4.31 units on a scale Standard Error 0.39	-4.83 units on a scale Standard Error 0.40	-4.80 units on a scale Standard Error 0.46	—
Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B Behaviour Score: Change at Week 8	-4.47 units on a scale Standard Error 0.40	-4.80 units on a scale Standard Error 0.41	-5.09 units on a scale Standard Error 0.41	-5.83 units on a scale Standard Error 0.48	—

SECONDARY outcome

Timeframe: Weeks 2, 4, 6, and 8 of Phase B

Population: FAS included all participants randomized to the double-blind, 8-week treatment period (Phase B) who took at least 1 dose of double-blind study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. Number analyzed = participants evaluable at specified timepoint.

CDRS-R response was defined as a ≥50% decrease in CDRS-R total score, calculated as: (change from baseline \[Randomization\])/(baseline value - 17). The CDRS-R is a clinician-rated scale to measure the severity of depression in children and adolescents. The CDRS-R was rated by a clinician following interviews with the child and parent and consisted of 17 items out of which 3 items rated nonverbal observations (listless speech, hypoactivity, and depressed affect). Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. A rating of 1 indicated normal functioning and a higher number indicated a greater degree of depression. The total score ranged from 17 (normal) to 113 (severe depression).

Outcome measures

Outcome measures
Measure	Double-Blind: Placebo n=153 Participants Participants received placebo capsules orally once daily for 8 weeks. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 10 mg n=147 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days and thereafter they received 10 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 20 mg n=146 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days, and thereafter they received vortioxetine 20 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Fluoxetine 20 mg n=80 Participants Participants initiated treatment with fluoxetine 10 mg/day orally for 6 days and thereafter they received 20 mg/day. for up to Week 8. Based on the tolerability, fluoxetine dose could be reduced by 10 mg/day at Week 4. Participants received 2 sessions of BPI also.	Vortioxetine Average (Avg. VOR) Avg. VOR is the average dose effect of the 2 vortioxetine doses (Vortioxetine 10 mg and Vortioxetine 20 mg).
Percentage of Participants With CDRS-R Response Week 2	7.8 percentage of participants	10.2 percentage of participants	11.6 percentage of participants	16.3 percentage of participants	—
Percentage of Participants With CDRS-R Response Week 4	20.7 percentage of participants	23.4 percentage of participants	26.6 percentage of participants	26.9 percentage of participants	—
Percentage of Participants With CDRS-R Response Week 6	30.8 percentage of participants	31.6 percentage of participants	37.2 percentage of participants	33.3 percentage of participants	—
Percentage of Participants With CDRS-R Response Week 8	29.4 percentage of participants	36.4 percentage of participants	41.0 percentage of participants	47.4 percentage of participants	—

SECONDARY outcome

Timeframe: Weeks 2, 4, 6, and 8 of Phase B

Population: FAS included all participants randomized to the double-blind, 8-week treatment period (Phase B) who took at least 1 dose of double-blind study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. Number analyzed = participants evaluable at specified timepoint.

CDRS-R remission was defined as a CDRS-R total score ≤28. The CDRS-R is a clinician-rated scale to measure the severity of depression in children and adolescents. The CDRS-R was rated by a clinician following interviews with the child and parent and consisted of 17 items out of which 3 items rated nonverbal observations (listless speech, hypoactivity, and depressed affect). Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. A rating of 1 indicated normal functioning and a higher number indicated a greater degree of depression. The total score ranged from 17 (normal) to 113 (severe depression).

Outcome measures

Outcome measures
Measure	Double-Blind: Placebo n=153 Participants Participants received placebo capsules orally once daily for 8 weeks. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 10 mg n=147 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days and thereafter they received 10 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 20 mg n=146 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days, and thereafter they received vortioxetine 20 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Fluoxetine 20 mg n=80 Participants Participants initiated treatment with fluoxetine 10 mg/day orally for 6 days and thereafter they received 20 mg/day. for up to Week 8. Based on the tolerability, fluoxetine dose could be reduced by 10 mg/day at Week 4. Participants received 2 sessions of BPI also.	Vortioxetine Average (Avg. VOR) Avg. VOR is the average dose effect of the 2 vortioxetine doses (Vortioxetine 10 mg and Vortioxetine 20 mg).
Percentage of Participants With CDRS-R Remission Week 2	2.0 percentage of participants	5.4 percentage of participants	2.7 percentage of participants	3.8 percentage of participants	—
Percentage of Participants With CDRS-R Remission Week 4	9.0 percentage of participants	9.5 percentage of participants	10.1 percentage of participants	9.0 percentage of participants	—
Percentage of Participants With CDRS-R Remission Week 6	14.7 percentage of participants	15.4 percentage of participants	15.3 percentage of participants	14.1 percentage of participants	—
Percentage of Participants With CDRS-R Remission Week 8	14.7 percentage of participants	16.7 percentage of participants	20.1 percentage of participants	26.9 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline (Week 4 of Phase A), Weeks 2, 4, 6, and 8 of Phase B

Population: FAS included all participants randomized to the double-blind, 8-week treatment period (Phase B) who took at least 1 dose of double-blind study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. Number analyzed = participants evaluable for specified categories.

The GBI 10-item depression scale was developed to screen for depressive symptoms in children and adolescents. Two versions of the GBI 10-item depression scale were used, the child rated version (CGBI) and the parent rated version (PGBI). The 10 depression items were rated on a 4-point scale from 0 (never or hardly ever) to 3 (very often or almost constantly). The total score ranged from 0 to 30, with higher scores indicating greater pathology.

Outcome measures

Outcome measures
Measure	Double-Blind: Placebo n=152 Participants Participants received placebo capsules orally once daily for 8 weeks. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 10 mg n=147 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days and thereafter they received 10 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 20 mg n=146 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days, and thereafter they received vortioxetine 20 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Fluoxetine 20 mg n=80 Participants Participants initiated treatment with fluoxetine 10 mg/day orally for 6 days and thereafter they received 20 mg/day. for up to Week 8. Based on the tolerability, fluoxetine dose could be reduced by 10 mg/day at Week 4. Participants received 2 sessions of BPI also.	Vortioxetine Average (Avg. VOR) Avg. VOR is the average dose effect of the 2 vortioxetine doses (Vortioxetine 10 mg and Vortioxetine 20 mg).
Change From Baseline in General Behaviour Inventory (GBI) Depression Subscale Score, Using the 10-Item Depression Subscale Assessed by Parent (PGBI-10D) and Child (CGBI-10D) at Weeks 2, 4, 6, and 8 of Phase B PGBI: Change at Week 2	-3.33 units on a scale Standard Error 0.55	-3.38 units on a scale Standard Error 0.55	-3.78 units on a scale Standard Error 0.56	-3.78 units on a scale Standard Error 0.63	—
Change From Baseline in General Behaviour Inventory (GBI) Depression Subscale Score, Using the 10-Item Depression Subscale Assessed by Parent (PGBI-10D) and Child (CGBI-10D) at Weeks 2, 4, 6, and 8 of Phase B PGBI: Change at Week 4	-4.11 units on a scale Standard Error 0.58	-4.72 units on a scale Standard Error 0.59	-5.33 units on a scale Standard Error 0.59	-4.45 units on a scale Standard Error 0.68	—
Change From Baseline in General Behaviour Inventory (GBI) Depression Subscale Score, Using the 10-Item Depression Subscale Assessed by Parent (PGBI-10D) and Child (CGBI-10D) at Weeks 2, 4, 6, and 8 of Phase B PGBI: Change at Week 6	-5.32 units on a scale Standard Error 0.58	-5.58 units on a scale Standard Error 0.59	-5.82 units on a scale Standard Error 0.59	-6.05 units on a scale Standard Error 0.68	—
Change From Baseline in General Behaviour Inventory (GBI) Depression Subscale Score, Using the 10-Item Depression Subscale Assessed by Parent (PGBI-10D) and Child (CGBI-10D) at Weeks 2, 4, 6, and 8 of Phase B PGBI: Change at Week 8	-5.81 units on a scale Standard Error 0.61	-6.51 units on a scale Standard Error 0.62	-6.46 units on a scale Standard Error 0.62	-6.56 units on a scale Standard Error 0.72	—
Change From Baseline in General Behaviour Inventory (GBI) Depression Subscale Score, Using the 10-Item Depression Subscale Assessed by Parent (PGBI-10D) and Child (CGBI-10D) at Weeks 2, 4, 6, and 8 of Phase B CGBI: Change at Week 2	-2.66 units on a scale Standard Error 0.61	-3.32 units on a scale Standard Error 0.61	-3.27 units on a scale Standard Error 0.61	-2.94 units on a scale Standard Error 0.70	—
Change From Baseline in General Behaviour Inventory (GBI) Depression Subscale Score, Using the 10-Item Depression Subscale Assessed by Parent (PGBI-10D) and Child (CGBI-10D) at Weeks 2, 4, 6, and 8 of Phase B CGBI: Change at Week 4	-3.65 units on a scale Standard Error 0.65	-4.15 units on a scale Standard Error 0.65	-4.16 units on a scale Standard Error 0.65	-3.16 units on a scale Standard Error 0.76	—
Change From Baseline in General Behaviour Inventory (GBI) Depression Subscale Score, Using the 10-Item Depression Subscale Assessed by Parent (PGBI-10D) and Child (CGBI-10D) at Weeks 2, 4, 6, and 8 of Phase B CGBI: Change at Week 6	-4.62 units on a scale Standard Error 0.63	-5.43 units on a scale Standard Error 0.64	-5.17 units on a scale Standard Error 0.63	-5.14 units on a scale Standard Error 0.73	—
Change From Baseline in General Behaviour Inventory (GBI) Depression Subscale Score, Using the 10-Item Depression Subscale Assessed by Parent (PGBI-10D) and Child (CGBI-10D) at Weeks 2, 4, 6, and 8 of Phase B CGBI: Change at Week 8	-5.26 units on a scale Standard Error 0.65	-6.12 units on a scale Standard Error 0.66	-5.48 units on a scale Standard Error 0.65	-5.46 units on a scale Standard Error 0.76	—

SECONDARY outcome

Timeframe: Weeks 2, 4, 6, and 8 of Phase B

Population: FAS included all participants randomized to the double-blind, 8-week treatment period (Phase B) who took at least 1 dose of double-blind study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. Number analyzed = participants evaluable at specified timepoint.

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 symptoms using a 7-point scale ranging from 1 (very much improved) to 7 (very much worse).

Outcome measures

Outcome measures
Measure	Double-Blind: Placebo n=152 Participants Participants received placebo capsules orally once daily for 8 weeks. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 10 mg n=147 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days and thereafter they received 10 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 20 mg n=145 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days, and thereafter they received vortioxetine 20 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Fluoxetine 20 mg n=80 Participants Participants initiated treatment with fluoxetine 10 mg/day orally for 6 days and thereafter they received 20 mg/day. for up to Week 8. Based on the tolerability, fluoxetine dose could be reduced by 10 mg/day at Week 4. Participants received 2 sessions of BPI also.	Vortioxetine Average (Avg. VOR) Avg. VOR is the average dose effect of the 2 vortioxetine doses (Vortioxetine 10 mg and Vortioxetine 20 mg).
Parent Global Assessment (PGA) Score Week 2	3.31 units on a scale Standard Error 0.09	3.25 units on a scale Standard Error 0.09	3.18 units on a scale Standard Error 0.09	3.13 units on a scale Standard Error 0.11	—
Parent Global Assessment (PGA) Score Week 4	2.97 units on a scale Standard Error 0.10	2.90 units on a scale Standard Error 0.10	2.84 units on a scale Standard Error 0.10	2.90 units on a scale Standard Error 0.12	—
Parent Global Assessment (PGA) Score Week 6	2.73 units on a scale Standard Error 0.10	2.73 units on a scale Standard Error 0.10	2.68 units on a scale Standard Error 0.10	2.80 units on a scale Standard Error 0.12	—
Parent Global Assessment (PGA) Score Week 8	2.68 units on a scale Standard Error 0.11	2.62 units on a scale Standard Error 0.11	2.61 units on a scale Standard Error 0.11	2.59 units on a scale Standard Error 0.13	—

SECONDARY outcome

Timeframe: Baseline (Week 4 of Phase A), Weeks 1, 2, 3, 4, 6, and 8 of Phase B

Population: FAS included all participants randomized to the double-blind, 8-week treatment period (Phase B) who took at least 1 dose of double-blind study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. Number analyzed = participants evaluable at specified timepoint.

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

Outcome measures

Outcome measures
Measure	Double-Blind: Placebo n=153 Participants Participants received placebo capsules orally once daily for 8 weeks. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 10 mg n=148 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days and thereafter they received 10 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 20 mg n=146 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days, and thereafter they received vortioxetine 20 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Fluoxetine 20 mg n=81 Participants Participants initiated treatment with fluoxetine 10 mg/day orally for 6 days and thereafter they received 20 mg/day. for up to Week 8. Based on the tolerability, fluoxetine dose could be reduced by 10 mg/day at Week 4. Participants received 2 sessions of BPI also.	Vortioxetine Average (Avg. VOR) Avg. VOR is the average dose effect of the 2 vortioxetine doses (Vortioxetine 10 mg and Vortioxetine 20 mg).
Change From Baseline in Clinical Global Impression - Severity of Illness (CGI-S) Score at Weeks 1, 2, 3, 4, 6, and 8 of Phase B Change at Week 1	-0.25 units on a scale Standard Error 0.07	-0.27 units on a scale Standard Error 0.07	-0.28 units on a scale Standard Error 0.07	-0.22 units on a scale Standard Error 0.08	—
Change From Baseline in Clinical Global Impression - Severity of Illness (CGI-S) Score at Weeks 1, 2, 3, 4, 6, and 8 of Phase B Change at Week 2	-0.50 units on a scale Standard Error 0.08	-0.60 units on a scale Standard Error 0.08	-0.65 units on a scale Standard Error 0.08	-0.63 units on a scale Standard Error 0.10	—
Change From Baseline in Clinical Global Impression - Severity of Illness (CGI-S) Score at Weeks 1, 2, 3, 4, 6, and 8 of Phase B Change at Week 3	-0.67 units on a scale Standard Error 0.08	-0.62 units on a scale Standard Error 0.08	-0.79 units on a scale Standard Error 0.08	-0.77 units on a scale Standard Error 0.10	—
Change From Baseline in Clinical Global Impression - Severity of Illness (CGI-S) Score at Weeks 1, 2, 3, 4, 6, and 8 of Phase B Change at Week 4	-0.95 units on a scale Standard Error 0.09	-1.00 units on a scale Standard Error 0.09	-1.06 units on a scale Standard Error 0.09	-1.01 units on a scale Standard Error 0.12	—
Change From Baseline in Clinical Global Impression - Severity of Illness (CGI-S) Score at Weeks 1, 2, 3, 4, 6, and 8 of Phase B Change at Week 6	-1.13 units on a scale Standard Error 0.10	-1.22 units on a scale Standard Error 0.10	-1.27 units on a scale Standard Error 0.10	-1.23 units on a scale Standard Error 0.12	—
Change From Baseline in Clinical Global Impression - Severity of Illness (CGI-S) Score at Weeks 1, 2, 3, 4, 6, and 8 of Phase B Change at Week 8	-1.31 units on a scale Standard Error 0.10	-1.40 units on a scale Standard Error 0.11	-1.44 units on a scale Standard Error 0.11	-1.57 units on a scale Standard Error 0.13	—

SECONDARY outcome

Timeframe: Weeks 1, 2, 3, 4, 6, and 8 of Phase B

Population: FAS included all participants randomized to the double-blind, 8-week treatment period (Phase B) who took at least 1 dose of double-blind study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. Number analyzed = participants evaluable at specified timepoint.

The CGI-I provides the clinician's impression of the participant's improvement (or worsening). The clinician assesses the participant's condition relative to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse).

Outcome measures

Outcome measures
Measure	Double-Blind: Placebo n=153 Participants Participants received placebo capsules orally once daily for 8 weeks. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 10 mg n=148 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days and thereafter they received 10 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Vortioxetine 20 mg n=145 Participants Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days, and thereafter they received vortioxetine 20 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.	Double-Blind: Fluoxetine 20 mg n=81 Participants Participants initiated treatment with fluoxetine 10 mg/day orally for 6 days and thereafter they received 20 mg/day. for up to Week 8. Based on the tolerability, fluoxetine dose could be reduced by 10 mg/day at Week 4. Participants received 2 sessions of BPI also.	Vortioxetine Average (Avg. VOR) Avg. VOR is the average dose effect of the 2 vortioxetine doses (Vortioxetine 10 mg and Vortioxetine 20 mg).
Clinical Global Impression - Global Improvement (CGI-I) Score Week 1	3.66 units on a scale Standard Error 0.07	3.63 units on a scale Standard Error 0.07	3.60 units on a scale Standard Error 0.07	3.72 units on a scale Standard Error 0.08	—
Clinical Global Impression - Global Improvement (CGI-I) Score Week 2	3.32 units on a scale Standard Error 0.08	3.30 units on a scale Standard Error 0.08	3.19 units on a scale Standard Error 0.08	3.26 units on a scale Standard Error 0.10	—
Clinical Global Impression - Global Improvement (CGI-I) Score Week 3	3.20 units on a scale Standard Error 0.08	3.20 units on a scale Standard Error 0.08	3.14 units on a scale Standard Error 0.08	3.23 units on a scale Standard Error 0.10	—
Clinical Global Impression - Global Improvement (CGI-I) Score Week 4	2.93 units on a scale Standard Error 0.09	2.93 units on a scale Standard Error 0.09	2.82 units on a scale Standard Error 0.09	2.97 units on a scale Standard Error 0.11	—
Clinical Global Impression - Global Improvement (CGI-I) Score Week 6	2.70 units on a scale Standard Error 0.09	2.64 units on a scale Standard Error 0.10	2.65 units on a scale Standard Error 0.10	2.78 units on a scale Standard Error 0.12	—
Clinical Global Impression - Global Improvement (CGI-I) Score Week 8	2.69 units on a scale Standard Error 0.10	2.58 units on a scale Standard Error 0.08	2.60 units on a scale Standard Error 0.10	2.57 units on a scale Standard Error 0.12	—

SECONDARY outcome

Timeframe: Weeks 1, 2, 3, 4, 6, and 8 of Phase B

Population: FAS included all participants randomized to the double-blind, 8-week treatment period (Phase B) who took at least 1 dose of double-blind study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Number analyzed = participants evaluable at specified timepoint.

CGI-S remission was defined as a CGI-S score of 1 or 2. The CGI-S provides the clinician's impression of the participant's current state of mental illness. The clinician uses his or her clinical experience of this participant population to rate the severity of the participant's current mental illness on a 7-point scale ranging from 1 (normal - not at all ill) to 7 (among the most extremely ill participants).