Trial Outcomes & Findings for A Safety Study in Participants With Major Depressive Disorder (NCT NCT01155661)

NCT ID: NCT01155661

Last Updated: 2018-04-17

Results Overview

A clinically significant effect was defined as a serious adverse event, regardless of causality. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 608 participants
• Primary outcome timeframe: Baseline through 54 weeks
• Results posted on: 2018-04-17

Participant Flow

There was a 54 week LY2216684 treatment Open-label Phase followed by 1 week Discontinuation Phase after abrupt discontinuation of treatment.

Participant milestones

Measure	LY2216684 + SSRI LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Overall Study STARTED	608
Overall Study COMPLETED	328
Overall Study NOT COMPLETED	280

Reasons for withdrawal

Measure	LY2216684 + SSRI LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Overall Study Adverse Event	101
Overall Study Death	1
Overall Study Lack of Efficacy	32
Overall Study Lost to Follow-up	22
Overall Study Physician Decision	3
Overall Study Protocol Violation	35
Overall Study Withdrawal by Subject	73
Overall Study Sponsor Decision	13

Baseline Characteristics

A Safety Study in Participants With Major Depressive Disorder

Baseline characteristics by cohort

Measure	LY2216684 + SSRI n=608 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Age, Continuous	47.54 years STANDARD_DEVIATION 12.97 • n=5 Participants
Sex: Female, Male Female	455 Participants n=5 Participants
Sex: Female, Male Male	153 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	214 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	320 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	74 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	14 Participants n=5 Participants
Race (NIH/OMB) Asian	5 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	59 Participants n=5 Participants
Race (NIH/OMB) White	521 Participants n=5 Participants
Race (NIH/OMB) More than one race	9 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	300 Participants n=5 Participants
Region of Enrollment Mexico	110 Participants n=5 Participants
Region of Enrollment Brazil	82 Participants n=5 Participants
Region of Enrollment Chile	50 Participants n=5 Participants
Region of Enrollment Lithuania	38 Participants n=5 Participants
Region of Enrollment Netherlands	19 Participants n=5 Participants
Region of Enrollment Spain	9 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline through 54 weeks

Population: All enrolled participants who did not discontinue from the study for the reason 'Lost to follow-up' at the first post-baseline visit.

A clinically significant effect was defined as a serious adverse event, regardless of causality.

A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.

Outcome measures

Measure	LY2216684 + SSRI n=600 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
The Number of Participants Experiencing Clinically Significant Effects	13 participants

SECONDARY outcome

Timeframe: Baseline through Week 54

Population: All enrolled participants with a baseline and at least one post-baseline C-SSRS value.

The C-SSRS captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation was defined as a "yes" answer to any 1 of 5 suicidal ideation questions, which included a wish to be dead and 4 different categories of active suicidal ideation. Suicidal behavior was defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide.

Outcome measures

Measure	LY2216684 + SSRI n=589 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Percent of Participants With Suicidal Ideation and Behavior Based on the Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation	11.71 percentage of participants
Percent of Participants With Suicidal Ideation and Behavior Based on the Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Behavior	0.17 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline ASEX total score value.

The ASEX scale was used to assess sexual functioning in both males and females. The ASEX total score for the male and female version was calculated as the sum of the responses (rated from 1 [extremely] to 6 [no/never]) to the 5 items of the ASEX scale. Total scores ranged from 5 to 30 with higher scores indicating greater sexual dysfunction. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for investigator, visit, baseline score, and baseline-by-visit.

Outcome measures

Measure	LY2216684 + SSRI n=537 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Change From Baseline to 54 Week Endpoint in the Arizona Sexual Experiences (ASEX) Scale	-2.28 units on a scale Standard Error 0.25

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline CPFQ total score value.

The CPFQ is a 7-item participant-rated questionnaire pertaining to a participant's cognitive and physical well-being. It assesses motivation, wakefulness, energy, focus, recall, word-finding difficulty, and mental acuity. Each item was scored on a 6-point scale ranging from 1 (greater than normal) to 6 (totally absent). Total scores ranged from 7 to 42. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for investigator, visit, baseline score, and baseline-by-visit.

Outcome measures

Measure	LY2216684 + SSRI n=541 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Change From Baseline to 54 Week Endpoint in Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ)	-8.64 units on a scale Standard Error 0.30

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline MADRS individual item and total score value.

The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist. Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for investigator, visit, baseline score, and baseline-by-visit.

Outcome measures

Measure	LY2216684 + SSRI n=589 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items MADRS Item 4: Reduced Sleep	-1.97 units on a scale Standard Error 0.07
Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items MADRS Item 5: Reduced Appetite	-1.08 units on a scale Standard Error 0.04
Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items MADRS Item 1: Apparent Sadness	-2.17 units on a scale Standard Error 0.05
Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items MADRS Item 2: Reported Sadness	-2.38 units on a scale Standard Error 0.06
Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items MADRS Item 3: Inner Tension	-1.56 units on a scale Standard Error 0.06
Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items MADRS Item 6: Concentration Difficulties	-1.88 units on a scale Standard Error 0.06
Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items MADRS Item 7: Lassitude	-2.18 units on a scale Standard Error 0.06
Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items MADRS Item 8: Inability to Feel	-2.22 units on a scale Standard Error 0.06
Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items MADRS Item 9: Pessimistic Thoughts	-1.52 units on a scale Standard Error 0.05
Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items MADRS Item 10: Suicidal Thoughts	-0.26 units on a scale Standard Error 0.02
Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items MADRS Total Score	-16.97 units on a scale Standard Error 0.41

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline Hospital Anxiety and Depression Scale (HADS) depression subscale value.

The Hospital Anxiety and Depression Scale (HADS) is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and depression subscales. Scores of 11 or more on either subscale are considered to be a significant 'case' of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7, 'normal.' Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for investigator, visit, baseline score, and baseline-by-visit.

Outcome measures

Measure	LY2216684 + SSRI n=588 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Change From Baseline to 54 Week Endpoint in Hospital Anxiety and Depression Scale (HADS) Depression Subscale Score	-6.32 units on a scale Standard Error 0.21

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline Clinical Global Impression - Severity (CGI-S) value.

Clinical Global Impression - Severity (CGI-S) measures severity of depression at the time of assessment compared with the start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for investigator, visit, baseline score, and baseline-by-visit.

Outcome measures

Measure	LY2216684 + SSRI n=589 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Change From Baseline to 54 Week Endpoint in Clinical Global Impression - Severity (CGI-S)	-2.17 units on a scale Standard Error 0.06

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline Fatigue Associated with Depression (FAsD) average score and subscale score.

The Fatigue Associated with Depression (FAsD) is a participant-rated scale with a total of 13 items. Six of the 13 items ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Seven of the 13 items ask how often fatigue impacts various aspects of the participant's lives with responses from 1 (not at all) to 5 (very much). The "Experience Score" was derived by taking the mean of Items 1 through 6, the "Impact Score" was derived by taking the mean of Items 7 through 13 (applicable items only), and the "Average Score" was the mean of Items 1 through 13 (derived by taking the mean of all applicable items for each participant). Item 12 applied only to participants with a spouse or significant other and Item 13 applied to participants who had a job or who went to school. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for investigator, visit, baseline score, and baseline-by-visit.

Outcome measures

Measure	LY2216684 + SSRI n=541 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Change From Baseline to 54 Week Endpoint in Fatigue Associated With Depression (FAsD) Average Score and Subscale Scores FAsD Experience Score	-1.25 units on a scale Standard Error 0.05
Change From Baseline to 54 Week Endpoint in Fatigue Associated With Depression (FAsD) Average Score and Subscale Scores FAsD Impact Score	-1.37 units on a scale Standard Error 0.05
Change From Baseline to 54 Week Endpoint in Fatigue Associated With Depression (FAsD) Average Score and Subscale Scores FAsD Average Score	-1.30 units on a scale Standard Error 0.05

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score value.

Response criteria was defined as at least a 50% decrease from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist. Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). This analysis models the probability of response at each visit, and the estimated probabilities were adjusted for visit and the baseline MADRS total score.

Outcome measures

Measure	LY2216684 + SSRI n=589 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Probability of Meeting the Response Criteria for Depressive Symptoms at Week 54 Endpoint	0.772 Probability of response 0.020

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score value.

Remission criteria was defined as a Montgomery-Asberg Depression Rating Scale (MADRS) total score of <= 10. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist. Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). This analysis models the probability of remission at each visit, and the estimated probabilities were adjusted for visit and the baseline MADRS total score.

Outcome measures

Measure	LY2216684 + SSRI n=589 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Probability of Meeting the Remission Criteria for Depressive Symptoms at Week 54 Endpoint	0.758 Probability of remission 0.022

SECONDARY outcome

Timeframe: Baseline, Week 8

Population: All enrolled participants with a baseline and at least one post-baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score value.

Response criteria was defined as at least a 50% decrease from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist. Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). The Kaplan-Meier product limit method of time to first response was calculated. In the calculation, participants who did not meet response criteria were considered as right-censored observations. The estimated percentage of participants who met response criteria by Week 8 from the Kaplan-Meier method is presented.

Outcome measures

Measure	LY2216684 + SSRI n=589 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Percentage of Participants Who Meet Response Criteria of Depressive Symptoms by Week 8	59.2 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline Hospital Anxiety and Depression Scale (HADS) anxiety subscale value.

The Hospital Anxiety and Depression Scale (HADS) is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item was rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and depression subscale. Scores of 11 or more on either subscale were considered to be a significant 'case' of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7, 'normal.' Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for investigator, visit, baseline score, and baseline-by-visit.

Outcome measures

Measure	LY2216684 + SSRI n=588 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Change From Baseline to 54 Week Endpoint in Hospital Anxiety and Depression Scale (HADS) Anxiety Subscale Score	-4.57 units on a scale Standard Error 0.18

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline Sheehan Disability Scale (SDS) subscale score.

The Sheehan Disability Scale (SDS) Global Functional Impairment Score (total score) and Subscores were completed by the participant and were used to assess the effect of the participant's symptoms on their work (Item 1), social (Item 2), and family life (Item 3). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. The Global Functional Impairment Score is the sum of the 3 items, and scores ranged from 0 to 30 with higher values indicating greater disruption in the participant's work life (work/school impairment [imp] score), social life (social life/leisure activities impairment [imp] score), and family life (family life/home responsibilities impairment [imp] score). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for investigator, visit, baseline score, and baseline-by-visit.

Outcome measures

Measure	LY2216684 + SSRI n=491 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Change From Baseline to 54 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscores SDS Global Functional Impairment(Imp) Score	-10.71 units on a scale Standard Error 0.37
Change From Baseline to 54 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscores Work/School Imp Score	-3.36 units on a scale Standard Error 0.15
Change From Baseline to 54 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscores Social Life/Leisure Activity Imp Score	-3.74 units on a scale Standard Error 0.13
Change From Baseline to 54 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscores Family Life/Home Responsibility Imp Score	-3.61 units on a scale Standard Error 0.13

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline EuroQol Questionnaire - 5 Dimension (EQ-5D) visual analog scale value.

The EQ-5D Visual Analog Scale is a generic, multidimensional, health-related, quality-of-life instrument. Overall health state score is self-reported using a visual analogue scale, marked on a scale of 0 to 100 with 0 representing worst imaginable health state and 100 representing best imaginable health state. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for investigator, visit, baseline score, and baseline-by-visit.

Outcome measures

Measure	LY2216684 + SSRI n=488 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Change From Baseline to 54 Week Endpoint in EuroQol Questionnaire - 5 Dimension (EQ-5D)	23.607 units on a scale Standard Error 1.019

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) percent of maximum possible score value.

The Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) is a self-administered 16 item questionnaire measuring degree of enjoyment and satisfaction experienced in various areas of daily life during the past week on a 5-point Likert scale (1=very poor and 5=very good). The total raw score is the sum of Items 1 to 14 and ranges from 14 to 70. The raw scores are converted to and expressed as the percentage of the maximum possible score. Higher scores indicate higher levels of enjoyment/satisfaction. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for investigator, visit, baseline score, and baseline-by-visit.

Outcome measures

Measure	LY2216684 + SSRI n=491 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Change From Baseline to 54 Week Endpoint in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF)	21.56 units on a scale Standard Error 0.90

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline Resource Utilization value.

The Resource Utilization (RU) form assesses the frequency and type of medical services (a primary care visit and/or a psychiatrist visit) that participants used within the previous year (for the baseline visit) or within approximately the previous 3 months (for post-baseline visits or the Week 54 endpoint). The percentage of participants who reported greater than zero number of primary care doctor visits and greater than zero number of psychiatrist visits is presented.

Outcome measures

Measure	LY2216684 + SSRI n=607 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Percentage of Participants Who Reported Resource Utilization (RU) at Baseline and at the Week 54 Endpoint Primary Care Doctor Visits, Baseline	62.27 percentage of participants
Percentage of Participants Who Reported Resource Utilization (RU) at Baseline and at the Week 54 Endpoint Primary Care Doctor Visits, Week 54	30.18 percentage of participants
Percentage of Participants Who Reported Resource Utilization (RU) at Baseline and at the Week 54 Endpoint Psychiatrist Visits, Baseline	44.15 percentage of participants
Percentage of Participants Who Reported Resource Utilization (RU) at Baseline and at the Week 54 Endpoint Psychiatrist Visits, Week 54	4.75 percentage of participants

SECONDARY outcome

Timeframe: Up to1 week after discontinuation of treatment

Population: All enrolled participants who abruptly discontinued LY2216684 (edivoxetine) treatment either at the end of the study or after early withdrawal from the study and who did not discontinue from the study for the reason 'Lost to follow-up' at the first post-baseline visit.

Discontinuation-emergent adverse events (DEAEs) were events that first occurred or worsened within 1-week after abrupt discontinuation of LY2216684 (edivoxetine) treatment.

Outcome measures

Measure	LY2216684 + SSRI n=472 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Percentage of Participants With Discontinuation-Emergent Adverse Events (DEAEs)	20.97 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 8

Population: All enrolled participants with a baseline and at least one post-baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score value.

Remission criteria was defined as a Montgomery-Asberg Depression Rating Scale (MADRS) total score of <= 10. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist. Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). The Kaplan-Meier product limit method of time to first remission was calculated. In the calculation, participants who did not meet remission criteria were considered as right-censored observations. The estimated percentage of participants who meet remission criteria by Week 8 from the Kaplan-Meier method is presented.

Outcome measures

Measure	LY2216684 + SSRI n=589 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Percentage of Participants Who Meet Remission Criteria of Depressive Symptoms by Week 8	47.7 percentage of participants

SECONDARY outcome

Timeframe: Weeks 2, 6, and 8

Population: All enrolled participants with at least one plasma sample.

Outcome measures

Measure	LY2216684 + SSRI n=512 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Plasma Concentration of LY2216684 12 mg dose	29.6 nanograms per milliliter (ng/mL) Standard Deviation 21.4
Plasma Concentration of LY2216684 18 mg dose	53.6 nanograms per milliliter (ng/mL) Standard Deviation 35.7

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants who did not discontinue from the study for the reason 'Lost to follow-up' at the first post-baseline visit.

A clinically significant effect was defined as a treatment-emergent adverse event; a reported adverse event that first occurred or worsened during the treatment phase. CYP2D6 predicted phenotype was classified as poor metabolizer (PM) or non-poor metabolizer (non-PM). The number of participants who reported at least one treatment-emergent adverse event is presented for each phenotype classification.

Outcome measures

Measure	LY2216684 + SSRI n=600 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
The Number of Participants Experiencing Clinically Significant Effects as a Function of CYP2D6 Predicted Phenotype at Week 54 Endpoint Poor Metabolizer	17 participants
The Number of Participants Experiencing Clinically Significant Effects as a Function of CYP2D6 Predicted Phenotype at Week 54 Endpoint Non-poor Metabolizer	408 participants

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline blood pressure value.

Blood pressure measurements were collected when the participant was in a sitting position. Three measurements of sitting blood pressure collected at approximately 1-minute intervals at every visit were averaged and used as the value for the visit. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for investigator, visit, baseline value, and baseline-by-visit.

Outcome measures

Measure	LY2216684 + SSRI n=590 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Change From Baseline to 54 Week Endpoint in Blood Pressure Sitting Systolic Blood Pressure	2.28 millimeters of mercury (mm Hg) Standard Error 0.50
Change From Baseline to 54 Week Endpoint in Blood Pressure Sitting Diastolic Blood Pressure	2.17 millimeters of mercury (mm Hg) Standard Error 0.40

SECONDARY outcome

Timeframe: Baseline, Week 54

Population: All enrolled participants with a baseline and at least one post-baseline pulse rate value.

Pulse measurements were collected when the participant was in a sitting position. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for investigator, visit, baseline value, and baseline-by-visit.

Outcome measures

Measure	LY2216684 + SSRI n=590 Participants LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Change From Baseline to Week 54 Endpoint in Pulse Rate	7.01 beats per minute (bpm) Standard Error 0.49

Adverse Events

LY2216684 + SSRI Open-Label Phase

Serious events: 13 serious events

Other events: 448 other events

Deaths: 0 deaths

Discontinuation Phase

Serious events: 0 serious events

Other events: 99 other events

Deaths: 0 deaths

Serious adverse events

Measure	LY2216684 + SSRI Open-Label Phase n=600 participants at risk LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI); included all enrolled participants who did not discontinue from the study for the reason 'Lost to follow-up' at the first post-baseline visit.	Discontinuation Phase n=472 participants at risk Included all enrolled participants who abruptly discontinued LY2216684 (edivoxetine) treatment either at the end of the study or after early withdrawal from the study and who did not discontinue from the study for the reason 'Lost to follow-up' at the discontinuation phase visit. All participants maintained their SSRI treatment at the stable dose during the discontinuation phase.
Cardiac disorders Myocardial infarction	0.17% 1/600 • Number of events 1	0.00% 0/472
Gastrointestinal disorders Colitis	0.17% 1/600 • Number of events 1	0.00% 0/472
Gastrointestinal disorders Large intestinal obstruction	0.17% 1/600 • Number of events 1	0.00% 0/472
Gastrointestinal disorders Oesophageal rupture	0.17% 1/600 • Number of events 1	0.00% 0/472
General disorders Non-cardiac chest pain	0.17% 1/600 • Number of events 1	0.00% 0/472
Infections and infestations Appendicitis	0.17% 1/600 • Number of events 1	0.00% 0/472
Infections and infestations Pharyngitis	0.17% 1/600 • Number of events 1	0.00% 0/472
Injury, poisoning and procedural complications Joint injury	0.17% 1/600 • Number of events 1	0.00% 0/472
Injury, poisoning and procedural complications Poisoning	0.17% 1/600 • Number of events 1	0.00% 0/472
Psychiatric disorders Mania	0.17% 1/600 • Number of events 1	0.00% 0/472
Psychiatric disorders Suicide attempt	0.17% 1/600 • Number of events 1	0.00% 0/472
Reproductive system and breast disorders Bartholinitis	0.22% 1/452 • Number of events 1	0.00% 0/362
Vascular disorders Hypertension	0.17% 1/600 • Number of events 1	0.00% 0/472

Other adverse events

Measure	LY2216684 + SSRI Open-Label Phase n=600 participants at risk LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI); included all enrolled participants who did not discontinue from the study for the reason 'Lost to follow-up' at the first post-baseline visit.	Discontinuation Phase n=472 participants at risk Included all enrolled participants who abruptly discontinued LY2216684 (edivoxetine) treatment either at the end of the study or after early withdrawal from the study and who did not discontinue from the study for the reason 'Lost to follow-up' at the discontinuation phase visit. All participants maintained their SSRI treatment at the stable dose during the discontinuation phase.
Cardiac disorders Palpitations	4.2% 25/600 • Number of events 26	0.85% 4/472 • Number of events 4
Gastrointestinal disorders Constipation	12.0% 72/600 • Number of events 77	0.00% 0/472
Gastrointestinal disorders Dry mouth	9.3% 56/600 • Number of events 58	0.42% 2/472 • Number of events 2
Gastrointestinal disorders Nausea	14.7% 88/600 • Number of events 99	2.5% 12/472 • Number of events 12
Gastrointestinal disorders Vomiting	6.7% 40/600 • Number of events 46	0.21% 1/472 • Number of events 1
General disorders Chills	3.5% 21/600 • Number of events 23	0.00% 0/472
Infections and infestations Influenza	3.5% 21/600 • Number of events 25	0.64% 3/472 • Number of events 3
Infections and infestations Nasopharyngitis	3.2% 19/600 • Number of events 22	0.42% 2/472 • Number of events 2
Infections and infestations Upper respiratory tract infection	5.7% 34/600 • Number of events 39	0.00% 0/472
Nervous system disorders Dizziness	7.5% 45/600 • Number of events 50	3.2% 15/472 • Number of events 18
Nervous system disorders Headache	11.3% 68/600 • Number of events 107	10.8% 51/472 • Number of events 59
Nervous system disorders Somnolence	3.5% 21/600 • Number of events 26	1.5% 7/472 • Number of events 7
Psychiatric disorders Anxiety	3.3% 20/600 • Number of events 23	1.5% 7/472 • Number of events 7
Psychiatric disorders Insomnia	6.0% 36/600 • Number of events 38	0.64% 3/472 • Number of events 3
Reproductive system and breast disorders Erectile dysfunction	4.7% 7/148 • Number of events 7	0.00% 0/110
Reproductive system and breast disorders Testicular pain	3.4% 5/148 • Number of events 5	0.00% 0/110
Skin and subcutaneous tissue disorders Hyperhidrosis	14.2% 85/600 • Number of events 93	0.64% 3/472 • Number of events 3
Vascular disorders Hypertension	3.8% 23/600 • Number of events 25	0.00% 0/472

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Results disclosure agreements

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

Restriction type: GT60