A Safety Study in Participants With Major Depressive Disorder

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01155661
• Collaborator: (none)
• Enrollment: 608
• Locations: 48
• Arm: 1
• Duration (Months): 26
• Patients Per Site: 12.7
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the long-term safety and tolerability of LY2216684 administered once daily (QD) in the adjunctive treatment with a selective serotonin reuptake inhibitor (SSRI) for up to approximately 1 year in participants with major depressive disorder (MDD) who are partial responders to their SSRI treatment.

Condition or Disease	Intervention/Treatment	Phase
Depressive Disorder, Major	Drug: LY2216684 (edivoxetine); Drug: SSRI	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 608 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Long-Term, Open-Label, Safety Study of LY2216684 12 to 18 mg Once Daily as Adjunctive Treatment for Patients With Major Depressive Disorder Who Are Partial Responders to Selective Serotonin Reuptake Inhibitor Treatment
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: LY2216684 (edivoxetine) + SSRI

Drug: LY2216684 (edivoxetine); 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI); Other Names: LY2216684 edivoxetine ; Drug: SSRI; Participants should have been on their SSRI for at least 6 weeks prior and were to continue on their stable dose throughout the study.; Other Names: Selective Serotonin Reuptake Inhibitor

Outcome Measures

Primary Outcome Measures

1. The Number of Participants Experiencing Clinically Significant Effects [Baseline through 54 weeks]

   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.

Secondary Outcome Measures

1. Percent of Participants With Suicidal Ideation and Behavior Based on the Columbia-Suicide Severity Rating Scale (C-SSRS) [Baseline through Week 54]

   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.

2. Change From Baseline to 54 Week Endpoint in the Arizona Sexual Experiences (ASEX) Scale [Baseline, Week 54]

   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.

3. Change From Baseline to 54 Week Endpoint in Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) [Baseline, Week 54]

   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.

4. Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items [Baseline, Week 54]

   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.

5. Change From Baseline to 54 Week Endpoint in Hospital Anxiety and Depression Scale (HADS) Depression Subscale Score [Baseline, Week 54]

   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.

6. Change From Baseline to 54 Week Endpoint in Clinical Global Impression - Severity (CGI-S) [Baseline, Week 54]

   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.

7. Change From Baseline to 54 Week Endpoint in Fatigue Associated With Depression (FAsD) Average Score and Subscale Scores [Baseline, Week 54]

   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.

8. Probability of Meeting the Response Criteria for Depressive Symptoms at Week 54 Endpoint [Baseline, Week 54]

   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.

9. Probability of Meeting the Remission Criteria for Depressive Symptoms at Week 54 Endpoint [Baseline, Week 54]

   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.

10. Percentage of Participants Who Meet Response Criteria of Depressive Symptoms by Week 8 [Baseline, Week 8]

    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.

11. Change From Baseline to 54 Week Endpoint in Hospital Anxiety and Depression Scale (HADS) Anxiety Subscale Score [Baseline, Week 54]

    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.

12. Change From Baseline to 54 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscores [Baseline, Week 54]

    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.

13. Change From Baseline to 54 Week Endpoint in EuroQol Questionnaire - 5 Dimension (EQ-5D) [Baseline, Week 54]

    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.

14. Change From Baseline to 54 Week Endpoint in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) [Baseline, Week 54]

    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.

15. Percentage of Participants Who Reported Resource Utilization (RU) at Baseline and at the Week 54 Endpoint [Baseline, Week 54]

    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.

16. Percentage of Participants With Discontinuation-Emergent Adverse Events (DEAEs) [Up to1 week after discontinuation of treatment]

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

17. Percentage of Participants Who Meet Remission Criteria of Depressive Symptoms by Week 8 [Baseline, Week 8]

    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.

18. Plasma Concentration of LY2216684 [Weeks 2, 6, and 8]

19. The Number of Participants Experiencing Clinically Significant Effects as a Function of CYP2D6 Predicted Phenotype at Week 54 Endpoint [Baseline, Week 54]

    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.

20. Change From Baseline to 54 Week Endpoint in Blood Pressure [Baseline, Week 54]

    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.

21. Change From Baseline to Week 54 Endpoint in Pulse Rate [Baseline, Week 54]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adults competent and able to give informed consent

• Women of child-bearing potential may participate but must test negative for pregnancy at the time of study entry; both women/men agree to use a reliable method of birth control

• Participants who are being treated with one of the following selective serotonin reuptake inhibitors (SSRIs): escitalopram, citalopram, sertraline, fluoxetine, paroxetine, and fluvoxamine; for at least 6 weeks prior to investigational product dispensing with at least the last 4 weeks at a stable, optimized dose

• Drug and dosage should be within the labeling guidelines for the specific country

• Meet criteria for Major Depressive Disorder (MDD), as defined by the Diagnostic and Statistical Manual, Fourth Edition, Text Revision (DSM-IV-TR) criteria

• Meet criteria for partial response, as defined by investigator's opinion that participant has experienced a minimal clinically meaningful improvement with SSRI

• Have a Grid Hamilton Rating Scale for Depression (GRID-HAMD17) total score greater than or equal to 16 at screening

• Have less than or equal to 75 percent improvement on the current SSRI at screening determined by the Massachusetts General Hospital Antidepressant Response Questionnaire (MGH-ATRQ)

• Meet all other inclusion criteria per protocol

Exclusion Criteria:

• Presence of another primary psychiatric illnesses:

• Have had or currently have any additional ongoing DSM-IV-TR Axis I condition other than major depression within 1 year of screening

• Have had any anxiety disorder that was considered a primary diagnosis within the past year (including panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, and social phobia, but excluding specific phobias)

• Have a current or previous diagnosis of a bipolar disorder, schizophrenia, or other psychotic disorder

• Have a history of substance abuse and/or dependence within the past 1 year (drug categories defined by DSM-IV-TR), not including caffeine and nicotine

• Have a DSM-IV-TR Axis II disorder that, in the judgment of the investigator, would interfere with compliance with protocol

• Unstable medical conditions that contraindicate the use of LY2216684

• Have any diagnosed medical condition which could be exacerbated by noradrenergic agents including unstable hypertension, unstable heart disease, tachycardia, tachyarrhythmia, narrow-angled glaucoma, urinary hesitation or retention

• Use of excluded concomitant or psychotropic medication other than SSRI

• Have initiated or discontinued hormone therapy within the previous 3 months of prior to enrollment

• History of treatment resistant depression as shown by:

• Have had lack of response of the current depressive episode to 2 or more adequate courses of antidepressant therapy at a clinically appropriate dose for at least 4 weeks, or in the judgment of the investigator, the participant has treatment-resistant depression

• Have a history of electroconvulsive therapy, transcranial magnetic stimulation, or psychosurgery within the last year

• Meet any other exclusion criteria per protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Birmingham	Alabama	United States	35216
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Little Rock	Arkansas	United States	72223
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Cerritos	California	United States	90703
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Irvine	California	United States	92618
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Los Alamitos	California	United States	90720
6	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Redlands	California	United States	92374
7	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Riverside	California	United States	92506
8	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	San Diego	California	United States	92121
9	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Upland	California	United States	91786
10	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Fort Walton Beach	Florida	United States	32547
11	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Gainesville	Florida	United States	32607
12	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Orlando	Florida	United States	32806
13	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Indianapolis	Indiana	United States	46260
14	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Prairie Village	Kansas	United States	66206
15	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Boston	Massachusetts	United States	02135
16	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Princeton	New Jersey	United States	08540
17	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Albuquerque	New Mexico	United States	87109
18	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Bronx	New York	United States	10467
19	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Mount Kisco	New York	United States	10549
20	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	New York	New York	United States	10021
21	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Rochester	New York	United States	14618
22	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Philadelphia	Pennsylvania	United States	19139
23	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Dallas	Texas	United States	75231
24	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	San Antonio	Texas	United States	78229
25	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Aparecida De Goiania		Brazil	74922-810
26	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Belo Horizonte		Brazil	30210420
27	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Botucatu		Brazil	18618 970
28	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Pelotas		Brazil	96030-000
29	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Ribeirão Preto		Brazil	14051-140
30	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Rio De Janeiro		Brazil	22270060
31	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Salvador		Brazil	40301500
32	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	São Paulo		Brazil	05403-010
33	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Antofagasta		Chile	1270244
34	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Santiago		Chile	7500710
35	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Kaunas		Lithuania	LT-3005
36	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Klaipeda		Lithuania	91251
37	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Leon		Mexico	37000
38	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Mazatlan		Mexico	82000
39	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Mexico City		Mexico	01030
40	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Monterrey		Mexico	64040
41	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	San Luis Potosi		Mexico	78250
42	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Villahermosa		Mexico	86035
43	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Zapopan		Mexico	45200
44	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Heerde		Netherlands	8181 CX
45	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Wildervank		Netherlands	9648 BE
46	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Alcala De Henares		Spain	28806
47	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Madrid		Spain	28029
48	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Zamora		Spain	49021

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01155661
• Other Study ID Numbers: 11318; H9P-MC-LNBO
• First Posted: Jul 2, 2010
• Last Update Posted: Apr 17, 2018
• Last Verified: Mar 1, 2018

• Additional relevant MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Phenylethyl Alcohol; Serotonin; Serotonin Uptake Inhibitors

Study Results

Participant Flow

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

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

Baseline Characteristics

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Overall Participants	608
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.54 (12.97)
Sex: Female, Male (Count of Participants)
Female	455 74.8%
Male	153 25.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	214 35.2%
Not Hispanic or Latino	320 52.6%
Unknown or Not Reported	74 12.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	14 2.3%
Asian	5 0.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	59 9.7%
White	521 85.7%
More than one race	9 1.5%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	300 49.3%
Mexico	110 18.1%
Brazil	82 13.5%
Chile	50 8.2%
Lithuania	38 6.3%
Netherlands	19 3.1%
Spain	9 1.5%

Outcome Measures

1. Primary Outcome

Title	The Number of Participants Experiencing Clinically Significant Effects
Description	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.
Time Frame	Baseline through 54 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	600
Number [participants]	13 2.1%

2. Secondary Outcome

Title	Percent of Participants With Suicidal Ideation and Behavior Based on the Columbia-Suicide Severity Rating Scale (C-SSRS)
Description	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.
Time Frame	Baseline through Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	589
Suicidal Ideation	11.71 1.9%
Suicidal Behavior	0.17 0%

3. Secondary Outcome

Title	Change From Baseline to 54 Week Endpoint in the Arizona Sexual Experiences (ASEX) Scale
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	537
Least Squares Mean (Standard Error) [units on a scale]	-2.28 (0.25)

4. Secondary Outcome

Title	Change From Baseline to 54 Week Endpoint in Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ)
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	541
Least Squares Mean (Standard Error) [units on a scale]	-8.64 (0.30)

5. Secondary Outcome

Title	Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	589
MADRS Item 1: Apparent Sadness	-2.17 (0.05)
MADRS Item 2: Reported Sadness	-2.38 (0.06)
MADRS Item 3: Inner Tension	-1.56 (0.06)
MADRS Item 4: Reduced Sleep	-1.97 (0.07)
MADRS Item 5: Reduced Appetite	-1.08 (0.04)
MADRS Item 6: Concentration Difficulties	-1.88 (0.06)
MADRS Item 7: Lassitude	-2.18 (0.06)
MADRS Item 8: Inability to Feel	-2.22 (0.06)
MADRS Item 9: Pessimistic Thoughts	-1.52 (0.05)
MADRS Item 10: Suicidal Thoughts	-0.26 (0.02)
MADRS Total Score	-16.97 (0.41)

6. Secondary Outcome

Title	Change From Baseline to 54 Week Endpoint in Hospital Anxiety and Depression Scale (HADS) Depression Subscale Score
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	588
Least Squares Mean (Standard Error) [units on a scale]	-6.32 (0.21)

7. Secondary Outcome

Title	Change From Baseline to 54 Week Endpoint in Clinical Global Impression - Severity (CGI-S)
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	589
Least Squares Mean (Standard Error) [units on a scale]	-2.17 (0.06)

8. Secondary Outcome

Title	Change From Baseline to 54 Week Endpoint in Fatigue Associated With Depression (FAsD) Average Score and Subscale Scores
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	541
FAsD Experience Score	-1.25 (0.05)
FAsD Impact Score	-1.37 (0.05)
FAsD Average Score	-1.30 (0.05)

9. Secondary Outcome

Title	Probability of Meeting the Response Criteria for Depressive Symptoms at Week 54 Endpoint
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	589
Number [Probability of response]	0.772 (0.020)

10. Secondary Outcome

Title	Probability of Meeting the Remission Criteria for Depressive Symptoms at Week 54 Endpoint
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	589
Number [Probability of remission]	0.758 (0.022)

11. Secondary Outcome

Title	Percentage of Participants Who Meet Response Criteria of Depressive Symptoms by Week 8
Description	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.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	589
Number [percentage of participants]	59.2 9.7%

12. Secondary Outcome

Title	Change From Baseline to 54 Week Endpoint in Hospital Anxiety and Depression Scale (HADS) Anxiety Subscale Score
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	588
Least Squares Mean (Standard Error) [units on a scale]	-4.57 (0.18)

13. Secondary Outcome

Title	Change From Baseline to 54 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscores
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	491
SDS Global Functional Impairment(Imp) Score	-10.71 (0.37)
Work/School Imp Score	-3.36 (0.15)
Social Life/Leisure Activity Imp Score	-3.74 (0.13)
Family Life/Home Responsibility Imp Score	-3.61 (0.13)

14. Secondary Outcome

Title	Change From Baseline to 54 Week Endpoint in EuroQol Questionnaire - 5 Dimension (EQ-5D)
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	488
Least Squares Mean (Standard Error) [units on a scale]	23.607 (1.019)

15. Secondary Outcome

Title	Change From Baseline to 54 Week Endpoint in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF)
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	491
Least Squares Mean (Standard Error) [units on a scale]	21.56 (0.90)

16. Secondary Outcome

Title	Percentage of Participants Who Reported Resource Utilization (RU) at Baseline and at the Week 54 Endpoint
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	607
Primary Care Doctor Visits, Baseline	62.27 10.2%
Primary Care Doctor Visits, Week 54	30.18 5%
Psychiatrist Visits, Baseline	44.15 7.3%
Psychiatrist Visits, Week 54	4.75 0.8%

17. Secondary Outcome

Title	Percentage of Participants With Discontinuation-Emergent Adverse Events (DEAEs)
Description	Discontinuation-emergent adverse events (DEAEs) were events that first occurred or worsened within 1-week after abrupt discontinuation of LY2216684 (edivoxetine) treatment.
Time Frame	Up to1 week after discontinuation of treatment

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	472
Number [percentage of participants]	20.97 3.4%

18. Secondary Outcome

Title	Percentage of Participants Who Meet Remission Criteria of Depressive Symptoms by Week 8
Description	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.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	589
Number [percentage of participants]	47.7 7.8%

19. Secondary Outcome

Title	Plasma Concentration of LY2216684
Time Frame	Weeks 2, 6, and 8

Outcome Measure Data

Analysis Population Description

All enrolled participants with at least one plasma sample.

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684: 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	512
12 mg dose	29.6 (21.4)
18 mg dose	53.6 (35.7)

20. Secondary Outcome

Title	The Number of Participants Experiencing Clinically Significant Effects as a Function of CYP2D6 Predicted Phenotype at Week 54 Endpoint
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	600
Poor Metabolizer	17 2.8%
Non-poor Metabolizer	408 67.1%

21. Secondary Outcome

Title	Change From Baseline to 54 Week Endpoint in Blood Pressure
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	590
Sitting Systolic Blood Pressure	2.28 (0.50)
Sitting Diastolic Blood Pressure	2.17 (0.40)

22. Secondary Outcome

Title	Change From Baseline to Week 54 Endpoint in Pulse Rate
Description	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.
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)
Measure Participants	590
Least Squares Mean (Standard Error) [beats per minute (bpm)]	7.01 (0.49)

Adverse Events

Arm/Group Title	LY2216684 + SSRI Open-Label Phase		Discontinuation Phase
Arm/Group Description	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.		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.
All Cause Mortality
	LY2216684 + SSRI Open-Label Phase		Discontinuation Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	LY2216684 + SSRI Open-Label Phase		Discontinuation Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/600 (2.2%)		0/472 (0%)
Cardiac disorders
Myocardial infarction	1/600 (0.2%)	1	0/472 (0%)	0
Gastrointestinal disorders
Colitis	1/600 (0.2%)	1	0/472 (0%)	0
Large intestinal obstruction	1/600 (0.2%)	1	0/472 (0%)	0
Oesophageal rupture	1/600 (0.2%)	1	0/472 (0%)	0
General disorders
Non-cardiac chest pain	1/600 (0.2%)	1	0/472 (0%)	0
Infections and infestations
Appendicitis	1/600 (0.2%)	1	0/472 (0%)	0
Pharyngitis	1/600 (0.2%)	1	0/472 (0%)	0
Injury, poisoning and procedural complications
Joint injury	1/600 (0.2%)	1	0/472 (0%)	0
Poisoning	1/600 (0.2%)	1	0/472 (0%)	0
Psychiatric disorders
Mania	1/600 (0.2%)	1	0/472 (0%)	0
Suicide attempt	1/600 (0.2%)	1	0/472 (0%)	0
Reproductive system and breast disorders
Bartholinitis	1/452 (0.2%)	1	0/362 (0%)	0
Vascular disorders
Hypertension	1/600 (0.2%)	1	0/472 (0%)	0
Other (Not Including Serious) Adverse Events
	LY2216684 + SSRI Open-Label Phase		Discontinuation Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	448/600 (74.7%)		99/472 (21%)
Cardiac disorders
Palpitations	25/600 (4.2%)	26	4/472 (0.8%)	4
Gastrointestinal disorders
Constipation	72/600 (12%)	77	0/472 (0%)	0
Dry mouth	56/600 (9.3%)	58	2/472 (0.4%)	2
Nausea	88/600 (14.7%)	99	12/472 (2.5%)	12
Vomiting	40/600 (6.7%)	46	1/472 (0.2%)	1
General disorders
Chills	21/600 (3.5%)	23	0/472 (0%)	0
Infections and infestations
Influenza	21/600 (3.5%)	25	3/472 (0.6%)	3
Nasopharyngitis	19/600 (3.2%)	22	2/472 (0.4%)	2
Upper respiratory tract infection	34/600 (5.7%)	39	0/472 (0%)	0
Nervous system disorders
Dizziness	45/600 (7.5%)	50	15/472 (3.2%)	18
Headache	68/600 (11.3%)	107	51/472 (10.8%)	59
Somnolence	21/600 (3.5%)	26	7/472 (1.5%)	7
Psychiatric disorders
Anxiety	20/600 (3.3%)	23	7/472 (1.5%)	7
Insomnia	36/600 (6%)	38	3/472 (0.6%)	3
Reproductive system and breast disorders
Erectile dysfunction	7/148 (4.7%)	7	0/110 (0%)	0
Testicular pain	5/148 (3.4%)	5	0/110 (0%)	0
Skin and subcutaneous tissue disorders
Hyperhidrosis	85/600 (14.2%)	93	3/472 (0.6%)	3
Vascular disorders
Hypertension	23/600 (3.8%)	25	0/472 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.