A Study of LY2216684 in Participants With Major Depression Disorder

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01370499
• Collaborator: (none)
• Enrollment: 288
• Locations: 9
• Arm: 1
• Duration (Months): 29
• Patients Per Site: 32
• Patients Per Site Per Month: 1.1

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 in the adjunctive treatment with an Selective Serotonin Reuptake Inhibitors (SSRI) for up to approximately 1 year in participants with Major Depressive Disorder (MDD) who were partial responders to their SSRI treatment.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 288 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 Adult Patients With Major Depressive Disorder Who Were Partial Responders to Selective Serotonin Reuptake Inhibitor Treatment
• Study Start Date: Aug 1, 2011
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: LY2216684 + SSRI LY2216684: 12 milligrams (mg) or 18 mg, administered orally, once daily for 52 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). During the open-label phase, all participants started at the 12 mg dose and could have the dose increased to 18 mg after the first week of treatment. During the first 12 weeks, participants were allowed (at scheduled or unscheduled visits) to decrease their dose to 12 mg based on response. After a decrease in dose to 12 mg, participants could have had an increase back up to 18 mg at any scheduled visit based on response and tolerability. After 12 weeks of treatment, participants maintained a stable dose. Open-label treatment was followed by a 1-week abrupt discontinuation phase. Participants who either completed study visits through Week 52 or discontinued early from the study for any reason returned 1 week later for follow-up visit. Participants did not receive LY2216684 but continued their SSRI treatment at a stable dose.

Drug: LY2216684; Other Names: Edivoxetine ; Drug: SSRI; Participants were to enter the study taking their current stable SSRI treatment dose and maintain the same dose throughout the study.; Other Names: Selective Serotonin Reuptake Inhibitor

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Clinically Significant Events [Baseline through 52 weeks]

   Clinically significant events were defined as serious adverse events, regardless of causality. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.

Secondary Outcome Measures

1. Percentage of Participants With Suicidal Behaviors and Ideations Measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) [Baseline through 52 weeks]

   The C-SSRS captures 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. Suicidal ideation was defined as treatment-emergent (TE) if not present at baseline. Percentage of participants was calculated by dividing the number of participants with suicide-related events by the total number of participants at risk, multiplied by 100%. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.

2. Change From Baseline to 52 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items [Baseline, 52 weeks]

   The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist (sadness [apparent], sadness [reported], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items are 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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.

3. Change From Baseline to 52 Week Endpoint in Clinical Global Impression - Severity (CGI-S) [Baseline, 52 weeks]

   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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.

4. Change From Baseline to 52 Week Endpoint in Fatigue Associated With Depression (FAsD) Average Score and Subscale Scores [Baseline, 52 weeks]

   The 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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.

5. Change From Baseline to 52 Week Endpoint in Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores [Baseline, 52 weeks]

   The Hospital Anxiety and Depression Scale (HADS) is a 14-item questionnaire with 2 subscales: anxiety and depression. The anxiety subscale score is the sum of the 7 odd-numbered items and depression subscale score is the sum of the 7 even-numbered items, giving maximum scores of 21 for each 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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.

6. Change From Baseline to 52 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscale Scores [Baseline, 52 weeks]

   The 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 his or her 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 high values indicating greater disruption in the participant's work life (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.

7. Change From Baseline to 52 Week Endpoint in EuroQol Questionnaire - 5 Dimension (EQ-5D) [Baseline, 52 weeks]

   The 5Q-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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.

8. Change From Baseline to 52 Week Endpoint in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) [Baseline, 52 weeks]

   The 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 possible scores range from 16 to 80. Higher scores indicate higher levels of enjoyment/satisfaction. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.

9. Change From Baseline to 52 Week Endpoint in Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) [Baseline, 52 weeks]

   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 is 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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.

10. Change From Baseline to 52 Week Endpoint in Arizona Sexual Experiences (ASEX) Scale [Baseline, 52 weeks]

    The Arizona Sexual Experiences (ASEX) scale is used to assess sexual functioning in both males and females. The ASEX total score for the male and female version is 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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.

11. Change From Baseline to 52 Week Endpoint in Blood Pressure [Baseline, 52 weeks]

    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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.

12. Change From Baseline to 52 Week Endpoint in Pulse Rate [Baseline, 52 weeks]

    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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Participants must have completed Study LNBM: NCT01173601 or Study LNBQ: NCT01187407

• Participants must be competent and able to give their own informed consent

Exclusion Criteria:

• Participants that have had or currently have any additional ongoing Diagnostic and Statistical Manual of Mental Disorder, fourth edition, text revision (DSM-IV-TR) Axis I condition other than major depression that was considered the primary diagnosis within 1 year of entering trial

• Participants that have had any anxiety disorder that was considered a primary diagnosis within the past year

• Participants that have a current or previous diagnosis of bipolar disorder, schizophrenia, or other psychotic disorder

• Participants that have a history of substance abuse within the past 1 year, and/or substance dependence within the past 1 year, not including caffeine and nicotine

• Participants that have an Axis II disorder that, in the judgment of the investigator, would interfere with compliance with the study

• Participants that have had a lack of full 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

• Participants that have a history of electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or psychosurgery within the last year

• Participants who are women who are pregnant or breastfeeding

• Participants who, in the opinion of the investigator, are judged to be at serious risk for harm to self or others

• Participants that have a serious or unstable medical illness

• Participants that have any diagnosed medical condition which could be exacerbated by noradrenergic agents

• Participants that have a history of severe allergies to more than 1 class of medication or multiple adverse drug reactions

• Participants that have a history of any seizure disorder (other than febrile seizures)

• Participants that have received treatment with a monoamine oxidase inhibitor (MAOI) within 14 days prior to entering trial or have a potential need to use an MAOI within 3 days after discontinuation from the study

• Participants that require psychotropic medication other than sedative/hypnotic medication for sleep

• Participants who are taking or have received treatment with any excluded medications within 7 days prior to entering trial

• Participants that have a thyroid stimulating hormone (TSH) level outside the laboratory established reference range. Participants previously diagnosed with hyperthyroidism or hypothyroidism who have been treated with a stable dose of thyroid supplement for at least the past 3 months, and who are clinically and chemically euthyroid will be allowed to participate in the study.

• Participants that have initiated or discontinued hormone therapy within the previous 3 months prior to enrollment

• Participants that have initiated psychotherapy, change in intensity of psychotherapy or other nondrug therapies (such as acupuncture or hypnosis) within 6 weeks prior to enrollment or at any time during the study.

• Participants have a positive urine drug screen (UDS) for any substances of abuse on entering trial

• Participants have significantly violated rules that a participant must comply with during Study LNBM: NCT01173601 or Study LNBQ: NCT01187407

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.	Chiba		Japan	270-0014
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.	Fukuoka		Japan	800-0226
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.	Fukushima		Japan	961-0021
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.	Hokkaido		Japan	0600-0004
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.	Hyogo		Japan	660-0882
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.	Kanagawa		Japan	238-0042
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.	Nagano		Japan	399-8301
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.	Saga		Japan	843-0023
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.	Tokyo		Japan	170-0002

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: NCT01370499
• Other Study ID Numbers: 12849; H9P-JE-LNDJ
• First Posted: Jun 10, 2011
• Last Update Posted: Oct 25, 2018
• Last Verified: Mar 1, 2018

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

Study Results

Participant Flow

Pre-assignment Detail	This is an open-label study with 1 treatment (12 or 18 milligrams [mg] LY2216684 + SSRI). However, the data were analyzed by the participants' treatment group from 2 parent studies (Study LNBM: NCT01173601 or Study LNBQ: NCT01187407). In these prior, parent studies, participants were randomized to receive Placebo + SSRI or LY2216684 + SSRI.

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI
Period Title: Overall Study
STARTED	195	93
Entered Abrupt Discontinuation Phase	188	85
Received at Least 1 Dose of Study Drug	195	92
COMPLETED	84	49
NOT COMPLETED	111	44

Baseline Characteristics

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)	Total
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	Total of all reporting groups
Overall Participants	195	93	288
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.28 (9.41)	37.40 (9.18)	38.68 (9.36)
Sex: Female, Male (Count of Participants)
Female	88 45.1%	45 48.4%	133 46.2%
Male	107 54.9%	48 51.6%	155 53.8%
Race/Ethnicity, Customized (Count of Participants)
Asian	195 100%	93 100%	288 100%
Region of Enrollment (Count of Participants)
Japan	195 100%	93 100%	288 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Clinically Significant Events
Description	Clinically significant events were defined as serious adverse events, regardless of causality. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.
Time Frame	Baseline through 52 weeks

Outcome Measure Data

Analysis Population Description

All participants who took at least one dose of study medication and did not discontinue from the study for the reason 'Lost to follow-up' at the first post-baseline visit.

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI
Measure Participants	195	92
Contusion	0 0%	1 1.1%
Hyperglycaemia	0 0%	1 1.1%
Subdural hygroma	1 0.5%	0 0%

2. Secondary Outcome

Title	Percentage of Participants With Suicidal Behaviors and Ideations Measured by the Columbia-Suicide Severity Rating Scale (C-SSRS)
Description	The C-SSRS captures 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. Suicidal ideation was defined as treatment-emergent (TE) if not present at baseline. Percentage of participants was calculated by dividing the number of participants with suicide-related events by the total number of participants at risk, multiplied by 100%. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.
Time Frame	Baseline through 52 weeks

Outcome Measure Data

Analysis Population Description

All participants who took at least one dose of study medication and had a baseline and at least one post-baseline value.

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI
Measure Participants	195	92
TE of suicidal ideation	8.72 4.5%	8.70 9.4%
Suicidal behavior	0.51 0.3%	0.00 0%

3. Secondary Outcome

Title	Change From Baseline to 52 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 has a 10-item checklist (sadness [apparent], sadness [reported], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items are 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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI
Measure Participants	195	93
MADRS total score	-4.33 (0.69)	-6.63 (1.00)
Apparent sadness	-0.36 (0.10)	-1.01 (0.16)
Reported sadness	-0.51 (0.12)	-0.92 (0.20)
Inner tension	-0.53 (0.10)	-0.85 (0.18)
Reduced sleep	-0.49 (0.12)	-0.33 (0.19)
Reduced appetite	-0.24 (0.08)	-0.25 (0.16)
Concentration difficulties	-0.72 (0.11)	-1.12 (0.17)
Lassitude	-0.71 (0.09)	-0.78 (0.16)
Inability to feel	-0.41 (0.11)	-0.77 (0.14)
Pessimistic thoughts	-0.31 (0.09)	-0.63 (0.14)
Suicidal thoughts	-0.19 (0.06)	-0.25 (0.07)

4. Secondary Outcome

Title	Change From Baseline to 52 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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI
Measure Participants	195	93
Least Squares Mean (Standard Error) [units on a scale]	-0.80 (0.10)	-0.78 (0.13)

5. Secondary Outcome

Title	Change From Baseline to 52 Week Endpoint in Fatigue Associated With Depression (FAsD) Average Score and Subscale Scores
Description	The 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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI
Measure Participants	183	86
Average score	-0.32 (0.07)	-0.18 (0.08)
Experience score	-0.28 (0.08)	-0.15 (0.09)
Impact score	-0.34 (0.07)	-0.19 (0.08)

6. Secondary Outcome

Title	Change From Baseline to 52 Week Endpoint in Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores
Description	The Hospital Anxiety and Depression Scale (HADS) is a 14-item questionnaire with 2 subscales: anxiety and depression. The anxiety subscale score is the sum of the 7 odd-numbered items and depression subscale score is the sum of the 7 even-numbered items, giving maximum scores of 21 for each 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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI
Measure Participants	189	87
Anxiety	-1.46 (0.28)	-0.55 (0.38)
Depression	-1.95 (0.34)	-1.24 (0.44)

7. Secondary Outcome

Title	Change From Baseline to 52 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscale Scores
Description	The 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 his or her 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 high values indicating greater disruption in the participant's work life (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI
Measure Participants	177	81
Global functional impairment score	-3.11 (0.63)	-2.37 (0.70)
Work impairment score	-0.98 (0.29)	-1.42 (0.42)
Social life impairment score	-1.01 (0.21)	-0.66 (0.25)
Family life impairment score	-1.10 (0.20)	-0.55 (0.24)

8. Secondary Outcome

Title	Change From Baseline to 52 Week Endpoint in EuroQol Questionnaire - 5 Dimension (EQ-5D)
Description	The 5Q-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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI
Measure Participants	177	81
Least Squares Mean (Standard Error) [units on a scale]	9.445 (1.846)	9.989 (2.288)

9. Secondary Outcome

Title	Change From Baseline to 52 Week Endpoint in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF)
Description	The 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 possible scores range from 16 to 80. Higher scores indicate higher levels of enjoyment/satisfaction. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI
Measure Participants	177	81
Least Squares Mean (Standard Error) [units on a scale]	6.28 (1.30)	5.19 (1.58)

10. Secondary Outcome

Title	Change From Baseline to 52 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 is 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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

All participants who took at least one dose of study medication and had a baseline and at least one post-baseline value.

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI
Measure Participants	183	86
Least Squares Mean (Standard Error) [units on a scale]	-4.02 (0.54)	-2.53 (0.75)

11. Secondary Outcome

Title	Change From Baseline to 52 Week Endpoint in Arizona Sexual Experiences (ASEX) Scale
Description	The Arizona Sexual Experiences (ASEX) scale is used to assess sexual functioning in both males and females. The ASEX total score for the male and female version is 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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

All participants who took at least one dose of study medication and had a baseline and at least one post-baseline value.

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI
Measure Participants	183	85
Least Squares Mean (Standard Error) [units on a scale]	-0.65 (0.39)	-0.40 (0.55)

12. Secondary Outcome

Title	Change From Baseline to 52 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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

All participants who took at least one dose of study medication and had a baseline and at least one post-baseline value.

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI
Measure Participants	195	92
Sitting systolic blood pressure	6.66 (0.93)	3.68 (1.28)
Sitting diastolic blood pressure	7.55 (0.83)	6.34 (1.03)

13. Secondary Outcome

Title	Change From Baseline to 52 Week 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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

All participants who took at least one dose of study medication and had a baseline and at least one post-baseline value.

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)	LY2216684 + SSRI (LY2216684 Prior Study)
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI
Measure Participants	195	92
Least Squares Mean (Standard Error) [beats per minute (bpm)]	17.00 (1.24)	10.98 (1.49)

Adverse Events

Arm/Group Title	LY2216684 + SSRI (Placebo Prior Study)		LY2216684 + SSRI (LY2216684 Prior Study)		LY2216684 + SSRI (Placebo Prior Study) DC Phase		LY2216684 + SSRI (LY2216684 Prior Study) DC Phase
Arm/Group Description	LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Includes all randomized participants who received at least 1 dose of study drug.		LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Includes all randomized participants who received at least 1 dose of study drug.		No study drug was administered. Participants were to maintain their selective serotonin reuptake inhibitor (SSRI) treatment at a stable dose for 1 week. Includes all randomized participants who received at least 1 dose of study drug and abruptly discontinued LY2216684 either at the end of the study or after early withdrawal from the study and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation (DC) Phase visit.		No study drug was administered. Participants were to maintain their SSRI treatment at a stable dose for 1 week. Includes all participants who received at least 1 dose of study drug and abruptly discontinued LY2216684 either at the end of the study or after early withdrawal from the study and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation (DC) Phase visit.
All Cause Mortality
	LY2216684 + SSRI (Placebo Prior Study)		LY2216684 + SSRI (LY2216684 Prior Study)		LY2216684 + SSRI (Placebo Prior Study) DC Phase		LY2216684 + SSRI (LY2216684 Prior Study) DC Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	LY2216684 + SSRI (Placebo Prior Study)		LY2216684 + SSRI (LY2216684 Prior Study)		LY2216684 + SSRI (Placebo Prior Study) DC Phase		LY2216684 + SSRI (LY2216684 Prior Study) DC Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/195 (0.5%)		2/92 (2.2%)		0/188 (0%)		0/84 (0%)
Injury, poisoning and procedural complications
Contusion	0/195 (0%)	0	1/92 (1.1%)	1	0/188 (0%)	0	0/84 (0%)	0
Metabolism and nutrition disorders
Hyperglycaemia	0/195 (0%)	0	1/92 (1.1%)	1	0/188 (0%)	0	0/84 (0%)	0
Nervous system disorders
Subdural hygroma	1/195 (0.5%)	1	0/92 (0%)	0	0/188 (0%)	0	0/84 (0%)	0
Other (Not Including Serious) Adverse Events
	LY2216684 + SSRI (Placebo Prior Study)		LY2216684 + SSRI (LY2216684 Prior Study)		LY2216684 + SSRI (Placebo Prior Study) DC Phase		LY2216684 + SSRI (LY2216684 Prior Study) DC Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	158/195 (81%)		67/92 (72.8%)		9/188 (4.8%)		3/84 (3.6%)
Cardiac disorders
Palpitations	36/195 (18.5%)	38	12/92 (13%)	12	2/188 (1.1%)	2	1/84 (1.2%)	1
Tachycardia	62/195 (31.8%)	77	17/92 (18.5%)	20	0/188 (0%)	0	0/84 (0%)	0
Gastrointestinal disorders
Constipation	19/195 (9.7%)	20	7/92 (7.6%)	7	0/188 (0%)	0	0/84 (0%)	0
Nausea	26/195 (13.3%)	29	8/92 (8.7%)	10	0/188 (0%)	0	1/84 (1.2%)	1
Vomiting	14/195 (7.2%)	14	3/92 (3.3%)	4	0/188 (0%)	0	0/84 (0%)	0
Infections and infestations
Nasopharyngitis	56/195 (28.7%)	94	29/92 (31.5%)	39	3/188 (1.6%)	3	0/84 (0%)	0
Investigations
Blood pressure increased	11/195 (5.6%)	11	0/92 (0%)	0	1/188 (0.5%)	1	1/84 (1.2%)	1
Heart rate increased	25/195 (12.8%)	31	7/92 (7.6%)	11	0/188 (0%)	0	0/84 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	4/195 (2.1%)	4	6/92 (6.5%)	7	0/188 (0%)	0	0/84 (0%)	0
Nervous system disorders
Dizziness	21/195 (10.8%)	28	4/92 (4.3%)	4	1/188 (0.5%)	1	0/84 (0%)	0
Headache	17/195 (8.7%)	45	7/92 (7.6%)	8	2/188 (1.1%)	2	1/84 (1.2%)	1
Renal and urinary disorders
Urinary hesitation	14/195 (7.2%)	14	0/92 (0%)	0	0/188 (0%)	0	0/84 (0%)	0
Urinary retention	10/195 (5.1%)	10	4/92 (4.3%)	4	0/188 (0%)	0	0/84 (0%)	0
Skin and subcutaneous tissue disorders
Hyperhidrosis	33/195 (16.9%)	33	16/92 (17.4%)	16	0/188 (0%)	0	0/84 (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.