Depressive Disorder, Major
Conditions
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.
Interventions
DRUGLY2216684 (edivoxetine)
12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)
DRUGSSRI
Participants should have been on their SSRI for at least 6 weeks prior and were to continue on their stable dose throughout the study.
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| Plasma Concentration of LY2216684 | Weeks 2, 6, and 8 | — |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Brazil, Chile, Lithuania, Mexico, Netherlands, Spain, United States
Participant flow
Pre-assignment details
There was a 54 week LY2216684 treatment Open-label Phase followed by 1 week Discontinuation Phase after abrupt discontinuation of treatment.
Participants by arm
| Arm | Count |
|---|---|
| LY2216684 + SSRI LY2216684 (edivoxetine): 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI) | 608 |
| Total | 608 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 101 |
| Overall Study | Death | 1 |
| Overall Study | Lack of Efficacy | 32 |
| Overall Study | Lost to Follow-up | 22 |
| Overall Study | Physician Decision | 3 |
| Overall Study | Protocol Violation | 35 |
| Overall Study | Sponsor Decision | 13 |
| Overall Study | Withdrawal by Subject | 73 |
Baseline characteristics
| Characteristic | LY2216684 + SSRI |
|---|---|
| Age, Continuous | 47.54 years STANDARD_DEVIATION 12.97 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 214 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 320 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 74 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 14 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 59 Participants |
| Race (NIH/OMB) More than one race | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 521 Participants |
| Region of Enrollment Brazil | 82 Participants |
| Region of Enrollment Chile | 50 Participants |
| Region of Enrollment Lithuania | 38 Participants |
| Region of Enrollment Mexico | 110 Participants |
| Region of Enrollment Netherlands | 19 Participants |
| Region of Enrollment Spain | 9 Participants |
| Region of Enrollment United States | 300 Participants |
| Sex: Female, Male Female | 455 Participants |
| Sex: Female, Male Male | 153 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 448 / 600 | 99 / 472 |
| serious Total, serious adverse events | 13 / 600 | 0 / 472 |
Outcome results
Primary
The Number of Participants Experiencing Clinically Significant Effects
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
Population: All enrolled participants who did not discontinue from the study for the reason 'Lost to follow-up' at the first post-baseline visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2216684 + SSRI | The Number of Participants Experiencing Clinically Significant Effects | 13 participants |
Secondary
Change From Baseline to 54 Week Endpoint in Blood Pressure
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
Population: All enrolled participants with a baseline and at least one post-baseline blood pressure value.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Blood Pressure | Sitting Systolic Blood Pressure | 2.28 millimeters of mercury (mm Hg) | Standard Error 0.5 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Blood Pressure | Sitting Diastolic Blood Pressure | 2.17 millimeters of mercury (mm Hg) | Standard Error 0.4 |
Secondary
Change From Baseline to 54 Week Endpoint in Clinical Global Impression - Severity (CGI-S)
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
Population: All enrolled participants with a baseline and at least one post-baseline Clinical Global Impression - Severity (CGI-S) value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Clinical Global Impression - Severity (CGI-S) | -2.17 units on a scale | Standard Error 0.06 |
Secondary
Change From Baseline to 54 Week Endpoint in EuroQol Questionnaire - 5 Dimension (EQ-5D)
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
Population: All enrolled participants with a baseline and at least one post-baseline EuroQol Questionnaire - 5 Dimension (EQ-5D) visual analog scale value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in EuroQol Questionnaire - 5 Dimension (EQ-5D) | 23.607 units on a scale | Standard Error 1.019 |
Secondary
Change From Baseline to 54 Week Endpoint in Fatigue Associated With Depression (FAsD) Average Score and Subscale Scores
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
Population: All enrolled participants with a baseline and at least one post-baseline Fatigue Associated with Depression (FAsD) average score and subscale score.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Fatigue Associated With Depression (FAsD) Average Score and Subscale Scores | FAsD Experience Score | -1.25 units on a scale | Standard Error 0.05 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Fatigue Associated With Depression (FAsD) Average Score and Subscale Scores | FAsD Impact Score | -1.37 units on a scale | Standard Error 0.05 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Fatigue Associated With Depression (FAsD) Average Score and Subscale Scores | FAsD Average Score | -1.30 units on a scale | Standard Error 0.05 |
Secondary
Change From Baseline to 54 Week Endpoint in Hospital Anxiety and Depression Scale (HADS) Anxiety Subscale Score
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
Population: All enrolled participants with a baseline and at least one post-baseline Hospital Anxiety and Depression Scale (HADS) anxiety subscale value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Hospital Anxiety and Depression Scale (HADS) Anxiety Subscale Score | -4.57 units on a scale | Standard Error 0.18 |
Secondary
Change From Baseline to 54 Week Endpoint in Hospital Anxiety and Depression Scale (HADS) Depression Subscale Score
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
Population: All enrolled participants with a baseline and at least one post-baseline Hospital Anxiety and Depression Scale (HADS) depression subscale value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Hospital Anxiety and Depression Scale (HADS) Depression Subscale Score | -6.32 units on a scale | Standard Error 0.21 |
Secondary
Change From Baseline to 54 Week Endpoint in Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ)
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
Population: All enrolled participants with a baseline and at least one post-baseline CPFQ total score value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) | -8.64 units on a scale | Standard Error 0.3 |
Secondary
Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items
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
Population: All enrolled participants with a baseline and at least one post-baseline MADRS individual item and total score value.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items | MADRS Item 1: Apparent Sadness | -2.17 units on a scale | Standard Error 0.05 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items | MADRS Item 2: Reported Sadness | -2.38 units on a scale | Standard Error 0.06 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items | MADRS Item 3: Inner Tension | -1.56 units on a scale | Standard Error 0.06 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items | MADRS Item 4: Reduced Sleep | -1.97 units on a scale | Standard Error 0.07 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items | MADRS Item 5: Reduced Appetite | -1.08 units on a scale | Standard Error 0.04 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items | MADRS Item 6: Concentration Difficulties | -1.88 units on a scale | Standard Error 0.06 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items | MADRS Item 7: Lassitude | -2.18 units on a scale | Standard Error 0.06 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items | MADRS Item 8: Inability to Feel | -2.22 units on a scale | Standard Error 0.06 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items | MADRS Item 9: Pessimistic Thoughts | -1.52 units on a scale | Standard Error 0.05 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items | MADRS Item 10: Suicidal Thoughts | -0.26 units on a scale | Standard Error 0.02 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items | MADRS Total Score | -16.97 units on a scale | Standard Error 0.41 |
Secondary
Change From Baseline to 54 Week Endpoint in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF)
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
Population: All enrolled participants with a baseline and at least one post-baseline Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) percent of maximum possible score value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) | 21.56 units on a scale | Standard Error 0.9 |
Secondary
Change From Baseline to 54 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscores
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
Population: All enrolled participants with a baseline and at least one post-baseline Sheehan Disability Scale (SDS) subscale score.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscores | SDS Global Functional Impairment(Imp) Score | -10.71 units on a scale | Standard Error 0.37 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscores | Work/School Imp Score | -3.36 units on a scale | Standard Error 0.15 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscores | Social Life/Leisure Activity Imp Score | -3.74 units on a scale | Standard Error 0.13 |
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscores | Family Life/Home Responsibility Imp Score | -3.61 units on a scale | Standard Error 0.13 |
Secondary
Change From Baseline to 54 Week Endpoint in the Arizona Sexual Experiences (ASEX) Scale
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
Population: All enrolled participants with a baseline and at least one post-baseline ASEX total score value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline to 54 Week Endpoint in the Arizona Sexual Experiences (ASEX) Scale | -2.28 units on a scale | Standard Error 0.25 |
Secondary
Change From Baseline to Week 54 Endpoint in Pulse Rate
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
Population: All enrolled participants with a baseline and at least one post-baseline pulse rate value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline to Week 54 Endpoint in Pulse Rate | 7.01 beats per minute (bpm) | Standard Error 0.49 |
Secondary
Percentage of Participants Who Meet Remission Criteria of Depressive Symptoms by 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.
Time frame: Baseline, Week 8
Population: All enrolled participants with a baseline and at least one post-baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2216684 + SSRI | Percentage of Participants Who Meet Remission Criteria of Depressive Symptoms by Week 8 | 47.7 percentage of participants |
Secondary
Percentage of Participants Who Meet Response Criteria of Depressive Symptoms by 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.
Time frame: Baseline, Week 8
Population: All enrolled participants with a baseline and at least one post-baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2216684 + SSRI | Percentage of Participants Who Meet Response Criteria of Depressive Symptoms by Week 8 | 59.2 percentage of participants |
Secondary
Percentage of Participants Who Reported Resource Utilization (RU) at Baseline and at the Week 54 Endpoint
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
Population: All enrolled participants with a baseline and at least one post-baseline Resource Utilization value.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LY2216684 + SSRI | Percentage of Participants Who Reported Resource Utilization (RU) at Baseline and at the Week 54 Endpoint | Primary Care Doctor Visits, Baseline | 62.27 percentage of participants |
| LY2216684 + SSRI | Percentage of Participants Who Reported Resource Utilization (RU) at Baseline and at the Week 54 Endpoint | Primary Care Doctor Visits, Week 54 | 30.18 percentage of participants |
| LY2216684 + SSRI | Percentage of Participants Who Reported Resource Utilization (RU) at Baseline and at the Week 54 Endpoint | Psychiatrist Visits, Baseline | 44.15 percentage of participants |
| LY2216684 + SSRI | Percentage of Participants Who Reported Resource Utilization (RU) at Baseline and at the Week 54 Endpoint | Psychiatrist Visits, Week 54 | 4.75 percentage of participants |
Secondary
Percentage of Participants With Discontinuation-Emergent Adverse Events (DEAEs)
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
Population: All enrolled participants who abruptly discontinued LY2216684 (edivoxetine) treatment either at the end of the study or after early withdrawal from the study and who did not discontinue from the study for the reason 'Lost to follow-up' at the first post-baseline visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2216684 + SSRI | Percentage of Participants With Discontinuation-Emergent Adverse Events (DEAEs) | 20.97 percentage of participants |
Secondary
Percent of Participants With Suicidal Ideation and Behavior Based on the Columbia-Suicide Severity Rating Scale (C-SSRS)
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
Population: All enrolled participants with a baseline and at least one post-baseline C-SSRS value.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LY2216684 + SSRI | Percent of Participants With Suicidal Ideation and Behavior Based on the Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation | 11.71 percentage of participants |
| LY2216684 + SSRI | Percent of Participants With Suicidal Ideation and Behavior Based on the Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Behavior | 0.17 percentage of participants |
Secondary
Plasma Concentration of LY2216684
Time frame: Weeks 2, 6, and 8
Population: All enrolled participants with at least one plasma sample.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Plasma Concentration of LY2216684 | 18 mg dose | 53.6 nanograms per milliliter (ng/mL) | Standard Deviation 35.7 |
| LY2216684 + SSRI | Plasma Concentration of LY2216684 | 12 mg dose | 29.6 nanograms per milliliter (ng/mL) | Standard Deviation 21.4 |
Secondary
Probability of Meeting the Remission Criteria for Depressive Symptoms at Week 54 Endpoint
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
Population: All enrolled participants with a baseline and at least one post-baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score value.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Probability of Meeting the Remission Criteria for Depressive Symptoms at Week 54 Endpoint | 0.758 Probability of remission | 0.022 |
Secondary
Probability of Meeting the Response Criteria for Depressive Symptoms at Week 54 Endpoint
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
Population: All enrolled participants with a baseline and at least one post-baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score value.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Probability of Meeting the Response Criteria for Depressive Symptoms at Week 54 Endpoint | 0.772 Probability of response | 0.02 |
Secondary
The Number of Participants Experiencing Clinically Significant Effects as a Function of CYP2D6 Predicted Phenotype at Week 54 Endpoint
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
Population: All enrolled participants who did not discontinue from the study for the reason 'Lost to follow-up' at the first post-baseline visit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LY2216684 + SSRI | The Number of Participants Experiencing Clinically Significant Effects as a Function of CYP2D6 Predicted Phenotype at Week 54 Endpoint | Poor Metabolizer | 17 participants |
| LY2216684 + SSRI | The Number of Participants Experiencing Clinically Significant Effects as a Function of CYP2D6 Predicted Phenotype at Week 54 Endpoint | Non-poor Metabolizer | 408 participants |