Depressive Disorder, Major
Conditions
Brief summary
The primary purpose is to study the efficacy, safety, and tolerability of LY2216684 as an adjunctive treatment for participants with major depressive disorder (MDD), who were identified as partial responders to an adequate course of treatment with a selective serotonin reuptake inhibitor (SSRI) (as defined by history).
Detailed description
This is a 12 week multi-center, double-blind, placebo-controlled study on the efficacy of LY2216684 augmentation of selective serotonin reuptake inhibitors (SSRIs) in participants with MDD who have a partial response to treatment with an SSRI. While remaining on a steady dose of their SSRI treatment at entry into the study, participants will be randomly assigned to adjunctive treatment with LY2216684 or placebo in a 1:1 ratio for 10 weeks of acute treatment.
Interventions
DRUGLY2216684
Starting dose is 6 milligrams (mg), then titrate up to 9 mg, 12 mg, or 18 mg (3 tablets) administered orally (PO), once daily (QD) for up to 10 weeks followed by a 2 week taper.
DRUGPlacebo
3 tablets PO QD for up to 12 weeks
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Meet criteria for major depressive disorder (MDD) as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision® (DSM-IV-TR criteria) * Meet criteria for partial response to an adequate course of treatment defined by the investigator's opinion that participant had attained at least minimal improvement on their current Selective serotonin reuptake inhibitor (SSRI) treatment * Women of child-bearing potential must test negative for pregnancy and agree to use a reliable method of birth control * Grid Hamilton Rating Scale for Depression (GRID-HAMD17) total score greater than or equal 16 to at both study entry and study enrollment * SSRI treatment for at least 6 weeks at a stable dose for at least 2 weeks prior to study enrollment * Stated participant preference for augmentation rather than switching antidepressant treatment
Exclusion criteria
* Are currently involved in or discontinued within the last 30 days from a clinical trial involving an off-label use of an investigational drug * Have previously completed or withdrawn from this study or any other study investigating LY2216684 * Have had or currently have any additional ongoing DSM-IV-TR Axis 1 condition other than MDD * Have had any anxiety disorder preceding the onset of depression that was considered the primary diagnosis within 1 year of study entry * Have a current or previous diagnosis of Bipolar I or II, psychotic depression, schizophrenia or other psychotic disorder * Have a history of substance abuse within the past 1 year * Have an Axis II disorder which, in the judgment of the investigator, would interfere with compliance with the protocol * Have had a 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 (ECT), transcranial magnetic stimulation (TMS), or psychosurgery within the last year * Women who are pregnant or breastfeeding * Participants who are judged to be at serious risk for harm to self or others * Have a serious or unstable medical illness * Have any diagnosed medical condition which could be exacerbated by noradrenergic agents including unstable hypertension, unstable heart disease, tachycardia or tachyarrhythmia, narrow angle glaucoma, or urinary hesitation or retention * Have a history of severe allergies to more than 1 class of medication or multiple adverse drug reactions * Have a history of any seizure disorder (other than febrile seizures) * Are taking noradrenergic psychotropic medications, such as tricyclic antidepressants or serotonin norepinephrine reuptake inhibitors (SNRI) * Have received treatment with a monoamine oxidase inhibitor (MAOI) within 14 days prior to study entry * Require psychotropic medication other than sedative/hypnotic medication for sleep * Are taking or have received treatment with any excluded medication within 7 days prior to study enrollment * Have a thyroid stimulating hormone (TSH ) level outside the established reference range * Have initiate or discontinued hormone therapy within the previous 3 months prior to enrollment * Initiation or change in intensity of psychotherapy or other non-drug therapies within 6 weeks prior to enrollment * A positive urine drug screen for any substance of abuse at study entry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 8 Weeks in Montgomery-Asberg Depression Rating Scale (MADRS) | Baseline, 8 weeks | The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS is a 10-item checklist with items rated on a scale of 0-6, for a total scores range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) means are calculated using mixed model repeating measures (MMRM) and adjusted for investigator, treatment-by-visit, baseline score, and baseline-by-visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Total Score | Baseline, 8 weeks | QIDS-SR16 is a 16-item, participant-rated measure of depressive symptomatology with 4 possible answers per question that are specific to the question. Each question (Q) is scored from 0 (no problems) to 3 (increased symptoms). The total score for each visit is the sum of 9 of the 16 items: the highest number from Q1-4 (sleep), number from Q5 (feeling sad), highest number from Q6-9 (appetite and weight), total for Q10-14 (concentration, view of self, thoughts of death or suicide, general interest and energy level respectively) and the highest number from Q15-16 (psychomotor changes). The total score ranges from 0 to 27 with higher scores indicating greater severity of depression. Least Squares (LS) means are calculated using mixed model repeating measures (MMRM) and adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. |
| Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Baseline, 8 weeks | QIDS-SR16 is a 16-item, participant-rated measure of depressive symptomatology with 4 possible answers per question that are specific to the question. Each question (Q) is scored from 0 (no problems) to 3 (increased symptoms). The total score for each visit is the sum of 9 of the 16 items: the highest number from Q1-4 (sleep), number from Q5 (feeling sad), highest number from Q6-9 (appetite and weight), total for Q10-14 (concentration, view of self, thoughts of death or suicide, general interest and energy level respectively) and the highest number from Q15-16 (psychomotor changes). Least Squares (LS) means are calculated using mixed model repeated measure (MMRM) and adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. |
| Change From Baseline to 8 Weeks in Hospital Anxiety and Depression Scale (HADS) | Baseline, up to 8 weeks | 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 each subscale. 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 is 'normal.' Least Squares (LS) means are calculated using analysis of covariance (ANCOVA) and adjusted for treatment, investigator, visit, treatment-by-visit, investigator, and baseline score. |
| Change From Baseline to 8 Weeks in Clinical Global Impression of Severity (CGI-S) | Baseline, 8 weeks | CGI-S measures severity of illness at the time of assessment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Least Squares (LS) means are calculated using mixed model repeated measures (MMRM) and adjusted for treatment, investigator, visit, treatment-by visit, baseline score, and baseline-by-visit. |
| Change From Baseline to 8 Weeks in Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) | Baseline, 8 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 score ranges from 7 to 42. Higher scores indicate greater disease severity. Least Squares (LS) means are calculated using mixed model repeated measures (MMRM) and adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. |
| Change From Baseline to 8 Weeks in Fatigue Associated With Depression Participant-Reported Outcome (FAsD PRO) | Baseline, up to 8 weeks | The FAsD PRO is a 16-item participant-rated scale. Seven items ask how often the participants experience different aspects of fatigue with each item rated on a 5-point scale: 1 (Never) to 5 (Always). Nine items ask how often fatigue impacts various aspects of the participants lives with each item rated on a 5-point scale: 1 (Not at all) to 5 (Very much). The Fatigue Experience Score is the mean of Items 1-5, and 7, the Fatigue Impact Score is the mean of Items 8-12, 14, and 16, and the Overall Average Score is the mean of Items 1-5, 7-12, 14 and 16. The Experience, Impact and Overall Mean Scores range from 1 to 5, lower scores indicate less experience/impact. Least Squares (LS) means are calculated using analysis of covariance (ANCOVA) and adjusted for treatment, investigator, and baseline score. |
| Change From Baseline to 8 Weeks Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ) | Baseline, up to 8 weeks | The MGH-SFQ is a 6-item participant-rated scale quantifying sexual interest, arousal (subjective excitement), ability to reach orgasm, erectile function (for males), and overall satisfaction and are scored on a 6-point scale: 1 (greater than normal) to 6 (totally absent); and overall improvement since last medication change is scored on a 6-point scale: 1 (very much improved) to 6 (much worse). Least Squares (LS) means are calculated using analysis of covariance (ANCOVA) and adjusted for treatment, investigator, and baseline score. |
| Colombia-Suicide Severity Rating Scale (C-SSRS) | Baseline, 8 weeks | Percent of participants with suicidal ideation, behavior and acts based on C-SSRS. The C-SSRS scale captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal behavior: a yes answer to any 1 of 5 suicidal behavior questions (preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide). Suicidal ideation: a yes answer to any 1 of 5 suicidal ideation questions (wish to be dead, and 4 different categories of active suicidal ideation). Suicidal act: a yes answer to actual attempt or completed suicide. |
| Change From Baseline to 8 Weeks in Visual Analog Scale for Fatigue (VAS-F) | Baseline, up to 8 weeks | VAS-F is a self-rated assessment on 2 items: the overall severity of fatigue and the interferences with daily activities due to fatigue. For the overall severity of fatigue the participant is asked to place a vertical mark on a 100 millimeter (mm) line between 2 anchors: 0 (not at all) and 100 (as severe as I can imagine). For the interference with daily activities due to fatigue, the participant is asked to place a vertical mark on a 100 mm line between 2 anchors: 0 (not at all) and 100 \[complete disability (unable to do any activities)\]. Least Squares (LS) means are calculated using analysis of covariance (ANCOVA) and adjusted for treatment, investigator, and baseline score. |
| Change From Baseline to 8 Weeks in Visual Analog Scale for Pain (VAS-P) | Baseline, up to 8 weeks | VAS-P is a self-rated assessment for 2 items: the overall severity of pain and the interferences with daily activities due to pain. For the overall severity of pain the participant is asked to place a vertical mark on a 100 millimeter (mm) line between 2 anchors: 0 (not at all) and 100 (as severe as I can imagine). For the interference with daily activities due to pain, the participant is asked to place a vertical mark on a 100-mm line between 2 anchors: 0 (not at all) and 100 \[complete disability (unable to do any activities)\]. Least Squares (LS) means are calculated using analysis of covariance (ANCOVA) and adjusted for treatment, investigator, and baseline score. |
| Change From Baseline to 8 Weeks in Sheehan Disability Scale (SDS) | Baseline, up to 8 weeks | The SDS is a 3-item, participant completed assessment and is used to assess the effect of the participant's symptoms on their work/social/family life. The Global Functional Impairment Total Score is a total of the 3 individual item scores, each with a scores range from 0 (not at all) to 10 (extremely). The Global Functional Impairment Total Scores range from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) means are calculated using analysis of covariance (ANCOVA) and adjusted for treatment, investigator, and baseline score. |
| Change From Baseline to 8 Weeks in Quality of Life Enjoyment and Satisfaction Survey-Short Form (Q-LES-Q-SF) | Baseline, up to 8 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, and is rated on a 5-point Likert scale: 1 (very poor) to 5 (very good). The Q-LES-Q-SF Total Raw Score is the sum of Items 1 to 14 and ranges from 14 to 70. The Q-LES-Q-SF 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 are calculated using analysis of covariance (ANCOVA) and adjusted for treatment, investigator, and baseline score. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 8 Weeks in Supine Systolic and Diastolic Blood Pressure | Baseline, 8 weeks | Blood pressure is collected while the participant is in the supine position. Least Squares (LS) means are calculated using mixed model repeated measures (MMRM) and adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. |
| Change From Baseline to 8 Weeks in Supine Pulse | Baseline, 8 weeks | Pulse is collected while the participant is in the supine position. Least Squares (LS) means are calculated using mixed model repeated measures (MMRM) and adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. |
Countries
United States
Participant flow
Pre-assignment details
In the Acute Treatment Phase participants are randomized to either LY2216684 or placebo treatment groups. Participants who complete the Acute Treatment Phase or discontinue early after 4 or more weeks in the Acute Treatment phase are eligible to participate in the 2 week Taper Phase, but not all elected to participate.
Participants by arm
| Arm | Count |
|---|---|
| LY2216684 LY2216684: Starting dose is 6 milligrams (mg), then titrated up to 9 mg, 12 mg, or 18 mg (3 tablets, varying in strength) administered orally (PO), once daily (QD) for up to 10 weeks followed by a 2-week Taper Phase. | 111 |
| Placebo Placebo: 3 tablets PO QD for up to 12 weeks. | 116 |
| Total | 227 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Acute Treatment Phase | Adverse Event | 6 | 8 |
| Acute Treatment Phase | Lack of Efficacy | 2 | 0 |
| Acute Treatment Phase | Lost to Follow-up | 5 | 12 |
| Acute Treatment Phase | Physician Decision | 0 | 1 |
| Acute Treatment Phase | Protocol Violation | 2 | 4 |
| Acute Treatment Phase | Withdrawal by Subject | 6 | 11 |
| Taper Phase | Adverse Event | 1 | 0 |
| Taper Phase | Lost to Follow-up | 1 | 1 |
| Taper Phase | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | LY2216684 | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 46.1 years STANDARD_DEVIATION 10.71 | 45.0 years STANDARD_DEVIATION 10.83 | 44.1 years STANDARD_DEVIATION 10.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 42 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 91 Participants | 185 Participants | 94 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 31 Participants | 61 Participants | 30 Participants |
| Race (NIH/OMB) More than one race | 7 Participants | 14 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) White | 67 Participants | 138 Participants | 71 Participants |
| Region of Enrollment United States | 111 Participants | 227 Participants | 116 Participants |
| Sex: Female, Male Female | 79 Participants | 158 Participants | 79 Participants |
| Sex: Female, Male Male | 32 Participants | 69 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 65 / 111 | 48 / 116 | 8 / 90 | 8 / 82 |
| serious Total, serious adverse events | 3 / 111 | 2 / 116 | 1 / 90 | 0 / 82 |
Outcome results
Primary
Change From Baseline to 8 Weeks in Montgomery-Asberg Depression Rating Scale (MADRS)
The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS is a 10-item checklist with items rated on a scale of 0-6, for a total scores range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) means are calculated using mixed model repeating measures (MMRM) and adjusted for investigator, treatment-by-visit, baseline score, and baseline-by-visit.
Time frame: Baseline, 8 weeks
Population: Intent-to-treat population analysis is determined by the treatment groups to which participants are randomly assigned regardless of treatment received, and includes all participants who do not meet response criteria during Weeks 1-2, have baseline and at least 1 post-baseline MADRS Total Score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 | Change From Baseline to 8 Weeks in Montgomery-Asberg Depression Rating Scale (MADRS) | -8.13 units on a scale | Standard Error 1.251 |
| Placebo | Change From Baseline to 8 Weeks in Montgomery-Asberg Depression Rating Scale (MADRS) | -5.76 units on a scale | Standard Error 1.249 |
Secondary
Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items
QIDS-SR16 is a 16-item, participant-rated measure of depressive symptomatology with 4 possible answers per question that are specific to the question. Each question (Q) is scored from 0 (no problems) to 3 (increased symptoms). The total score for each visit is the sum of 9 of the 16 items: the highest number from Q1-4 (sleep), number from Q5 (feeling sad), highest number from Q6-9 (appetite and weight), total for Q10-14 (concentration, view of self, thoughts of death or suicide, general interest and energy level respectively) and the highest number from Q15-16 (psychomotor changes). Least Squares (LS) means are calculated using mixed model repeated measure (MMRM) and adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time frame: Baseline, 8 weeks
Population: Intent-to-treat population analysis is determined by the treatment groups to which participants are randomly assigned regardless of treatment received, and includes all participants who do not meet response criteria during Weeks 1-2, have baseline and at least 1 post-baseline QIDS-SR16 Individual Score.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Item 5 | -0.88 units on a scale | Standard Error 0.124 |
| LY2216684 | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Item 12 | -0.21 units on a scale | Standard Error 0.048 |
| LY2216684 | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Item 10 | -0.61 units on a scale | Standard Error 0.094 |
| LY2216684 | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Item 13 | -0.55 units on a scale | Standard Error 0.139 |
| LY2216684 | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Highest Score from Items 6-9 | -0.32 units on a scale | Standard Error 0.131 |
| LY2216684 | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Item 14 | -0.65 units on a scale | Standard Error 0.109 |
| LY2216684 | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Item 11 | -0.77 units on a scale | Standard Error 0.127 |
| LY2216684 | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Highest Score from Items 15-16 | -0.53 units on a scale | Standard Error 0.129 |
| LY2216684 | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Highest Score from Items 1-4 | -0.49 units on a scale | Standard Error 0.113 |
| Placebo | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Highest Score from Items 15-16 | -0.14 units on a scale | Standard Error 0.13 |
| Placebo | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Highest Score from Items 1-4 | -0.26 units on a scale | Standard Error 0.115 |
| Placebo | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Item 5 | -0.45 units on a scale | Standard Error 0.126 |
| Placebo | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Highest Score from Items 6-9 | -0.29 units on a scale | Standard Error 0.133 |
| Placebo | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Item 10 | -0.33 units on a scale | Standard Error 0.095 |
| Placebo | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Item 11 | -0.39 units on a scale | Standard Error 0.129 |
| Placebo | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Item 12 | -0.19 units on a scale | Standard Error 0.049 |
| Placebo | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Item 13 | -0.48 units on a scale | Standard Error 0.14 |
| Placebo | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Individual Items | Item 14 | -0.28 units on a scale | Standard Error 0.11 |
Secondary
Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Total Score
QIDS-SR16 is a 16-item, participant-rated measure of depressive symptomatology with 4 possible answers per question that are specific to the question. Each question (Q) is scored from 0 (no problems) to 3 (increased symptoms). The total score for each visit is the sum of 9 of the 16 items: the highest number from Q1-4 (sleep), number from Q5 (feeling sad), highest number from Q6-9 (appetite and weight), total for Q10-14 (concentration, view of self, thoughts of death or suicide, general interest and energy level respectively) and the highest number from Q15-16 (psychomotor changes). The total score ranges from 0 to 27 with higher scores indicating greater severity of depression. Least Squares (LS) means are calculated using mixed model repeating measures (MMRM) and adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time frame: Baseline, 8 weeks
Population: Intent-to-treat population analysis is determined by the treatment groups to which participants are randomly assigned regardless of treatment received, and includes all participants who do not meet response criteria during Weeks 1-2, have baseline and at least 1 post-baseline QIDS-SR16 Total Score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Total Score | -4.71 units on a scale | Standard Error 0.625 |
| Placebo | Change From Baseline to 8 Weeks in 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) Total Score | -2.97 units on a scale | Standard Error 0.628 |
Secondary
Change From Baseline to 8 Weeks in Clinical Global Impression of Severity (CGI-S)
CGI-S measures severity of illness at the time of assessment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Least Squares (LS) means are calculated using mixed model repeated measures (MMRM) and adjusted for treatment, investigator, visit, treatment-by visit, baseline score, and baseline-by-visit.
Time frame: Baseline, 8 weeks
Population: Intent-to-treat population analysis is determined by the treatment groups to which participants are randomly assigned regardless of treatment received, and includes all participants who do not meet response criteria during Weeks 1-2, have baseline and at least 1 post-baseline CGI-Severity Score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 | Change From Baseline to 8 Weeks in Clinical Global Impression of Severity (CGI-S) | -0.74 units on a scale | Standard Error 0.135 |
| Placebo | Change From Baseline to 8 Weeks in Clinical Global Impression of Severity (CGI-S) | -0.71 units on a scale | Standard Error 0.135 |
Secondary
Change From Baseline to 8 Weeks in Fatigue Associated With Depression Participant-Reported Outcome (FAsD PRO)
The FAsD PRO is a 16-item participant-rated scale. Seven items ask how often the participants experience different aspects of fatigue with each item rated on a 5-point scale: 1 (Never) to 5 (Always). Nine items ask how often fatigue impacts various aspects of the participants lives with each item rated on a 5-point scale: 1 (Not at all) to 5 (Very much). The Fatigue Experience Score is the mean of Items 1-5, and 7, the Fatigue Impact Score is the mean of Items 8-12, 14, and 16, and the Overall Average Score is the mean of Items 1-5, 7-12, 14 and 16. The Experience, Impact and Overall Mean Scores range from 1 to 5, lower scores indicate less experience/impact. Least Squares (LS) means are calculated using analysis of covariance (ANCOVA) and adjusted for treatment, investigator, and baseline score.
Time frame: Baseline, up to 8 weeks
Population: Intent-to-treat population analysis is determined by the treatment groups to which participants are randomly assigned regardless of treatment received, and includes all participants who do not meet response criteria during Weeks 1-2, have baseline and at least 1 post-baseline FAsD-PRO Score; last observation carried forward (LOCF).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 | Change From Baseline to 8 Weeks in Fatigue Associated With Depression Participant-Reported Outcome (FAsD PRO) | Overall Average Score | -0.75 units on a scale | Standard Error 0.124 |
| LY2216684 | Change From Baseline to 8 Weeks in Fatigue Associated With Depression Participant-Reported Outcome (FAsD PRO) | Fatigue Experience Score | -0.60 units on a scale | Standard Error 0.126 |
| LY2216684 | Change From Baseline to 8 Weeks in Fatigue Associated With Depression Participant-Reported Outcome (FAsD PRO) | Fatigue Impact Score | -0.92 units on a scale | Standard Error 0.14 |
| Placebo | Change From Baseline to 8 Weeks in Fatigue Associated With Depression Participant-Reported Outcome (FAsD PRO) | Overall Average Score | -0.41 units on a scale | Standard Error 0.127 |
| Placebo | Change From Baseline to 8 Weeks in Fatigue Associated With Depression Participant-Reported Outcome (FAsD PRO) | Fatigue Experience Score | -0.42 units on a scale | Standard Error 0.129 |
| Placebo | Change From Baseline to 8 Weeks in Fatigue Associated With Depression Participant-Reported Outcome (FAsD PRO) | Fatigue Impact Score | -0.41 units on a scale | Standard Error 0.14 |
Secondary
Change From Baseline to 8 Weeks in Hospital Anxiety and Depression Scale (HADS)
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 each subscale. 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 is 'normal.' Least Squares (LS) means are calculated using analysis of covariance (ANCOVA) and adjusted for treatment, investigator, visit, treatment-by-visit, investigator, and baseline score.
Time frame: Baseline, up to 8 weeks
Population: Intent-to-treat population analysis is determined by the treatment groups to which participants are randomly assigned regardless of treatment received, and includes all participants who do not meet response criteria during Weeks 1-2, have baseline and at least 1 post-baseline HADS Score; last observation carried forward (LOCF).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 | Change From Baseline to 8 Weeks in Hospital Anxiety and Depression Scale (HADS) | Anxiety Subscale Score | -2.19 units on a scale | Standard Error 0.484 |
| LY2216684 | Change From Baseline to 8 Weeks in Hospital Anxiety and Depression Scale (HADS) | Depression Subscale Score | -3.28 units on a scale | Standard Error 0.549 |
| Placebo | Change From Baseline to 8 Weeks in Hospital Anxiety and Depression Scale (HADS) | Anxiety Subscale Score | -1.42 units on a scale | Standard Error 0.483 |
| Placebo | Change From Baseline to 8 Weeks in Hospital Anxiety and Depression Scale (HADS) | Depression Subscale Score | -1.93 units on a scale | Standard Error 0.551 |
Secondary
Change From Baseline to 8 Weeks 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 is scored on a 6-point scale ranging from 1 (greater than normal) to 6 (totally absent). Total score ranges from 7 to 42. Higher scores indicate greater disease severity. Least Squares (LS) means are calculated using mixed model repeated measures (MMRM) and adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time frame: Baseline, 8 weeks
Population: Intent-to-treat population analysis is determined by the treatment groups to which participants are randomly assigned regardless of treatment received, and includes all participants who do not meet response criteria during Weeks 1-2, have baseline and at least 1 post-baseline CPFQ Total Score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 | Change From Baseline to 8 Weeks in Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) | -5.69 units on a scale | Standard Error 0.831 |
| Placebo | Change From Baseline to 8 Weeks in Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) | -2.62 units on a scale | Standard Error 0.833 |
Secondary
Change From Baseline to 8 Weeks in Quality of Life Enjoyment and Satisfaction Survey-Short Form (Q-LES-Q-SF)
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, and is rated on a 5-point Likert scale: 1 (very poor) to 5 (very good). The Q-LES-Q-SF Total Raw Score is the sum of Items 1 to 14 and ranges from 14 to 70. The Q-LES-Q-SF 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 are calculated using analysis of covariance (ANCOVA) and adjusted for treatment, investigator, and baseline score.
Time frame: Baseline, up to 8 weeks
Population: Intent-to-treat analysis is determined by treatment group participants are randomly assigned regardless of treatment received, includes all participants who do not respond in Weeks 1-2, have baseline and at least 1 post-baseline Q-LES-Q-SF Total Score; last observation carried forward. If ≤2 items are missing mean of all other items are imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 | Change From Baseline to 8 Weeks in Quality of Life Enjoyment and Satisfaction Survey-Short Form (Q-LES-Q-SF) | 12.94 percentage of the maximum possible score | Standard Error 2.073 |
| Placebo | Change From Baseline to 8 Weeks in Quality of Life Enjoyment and Satisfaction Survey-Short Form (Q-LES-Q-SF) | 5.44 percentage of the maximum possible score | Standard Error 2.078 |
Secondary
Change From Baseline to 8 Weeks in Sheehan Disability Scale (SDS)
The SDS is a 3-item, participant completed assessment and is used to assess the effect of the participant's symptoms on their work/social/family life. The Global Functional Impairment Total Score is a total of the 3 individual item scores, each with a scores range from 0 (not at all) to 10 (extremely). The Global Functional Impairment Total Scores range from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) means are calculated using analysis of covariance (ANCOVA) and adjusted for treatment, investigator, and baseline score.
Time frame: Baseline, up to 8 weeks
Population: Intent-to-treat analysis is determined by treatment group participants are randomly assigned regardless of treatment received, includes all participants who do not respond in Weeks 1-2, have baseline and at least 1 post-baseline SDS Total Score; last observation carried forward. Missing work score imputed with average of other 2-item scores.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 | Change From Baseline to 8 Weeks in Sheehan Disability Scale (SDS) | -5.95 units on a scale | Standard Error 1.116 |
| Placebo | Change From Baseline to 8 Weeks in Sheehan Disability Scale (SDS) | -2.63 units on a scale | Standard Error 1.123 |
Secondary
Change From Baseline to 8 Weeks in Visual Analog Scale for Fatigue (VAS-F)
VAS-F is a self-rated assessment on 2 items: the overall severity of fatigue and the interferences with daily activities due to fatigue. For the overall severity of fatigue the participant is asked to place a vertical mark on a 100 millimeter (mm) line between 2 anchors: 0 (not at all) and 100 (as severe as I can imagine). For the interference with daily activities due to fatigue, the participant is asked to place a vertical mark on a 100 mm line between 2 anchors: 0 (not at all) and 100 \[complete disability (unable to do any activities)\]. Least Squares (LS) means are calculated using analysis of covariance (ANCOVA) and adjusted for treatment, investigator, and baseline score.
Time frame: Baseline, up to 8 weeks
Population: Intent-to-treat population analysis is determined by the treatment groups to which participants are randomly assigned regardless of treatment received, and includes all participants who do not meet response criteria during Weeks 1-2, have baseline and at least 1 post-baseline VAS-F Score; last observation carried forward (LOCF).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 | Change From Baseline to 8 Weeks in Visual Analog Scale for Fatigue (VAS-F) | Severity | -16.42 units on a scale | Standard Error 3.407 |
| LY2216684 | Change From Baseline to 8 Weeks in Visual Analog Scale for Fatigue (VAS-F) | Interference | -18.91 units on a scale | Standard Error 3.698 |
| Placebo | Change From Baseline to 8 Weeks in Visual Analog Scale for Fatigue (VAS-F) | Severity | -13.81 units on a scale | Standard Error 3.412 |
| Placebo | Change From Baseline to 8 Weeks in Visual Analog Scale for Fatigue (VAS-F) | Interference | -10.33 units on a scale | Standard Error 3.701 |
Secondary
Change From Baseline to 8 Weeks in Visual Analog Scale for Pain (VAS-P)
VAS-P is a self-rated assessment for 2 items: the overall severity of pain and the interferences with daily activities due to pain. For the overall severity of pain the participant is asked to place a vertical mark on a 100 millimeter (mm) line between 2 anchors: 0 (not at all) and 100 (as severe as I can imagine). For the interference with daily activities due to pain, the participant is asked to place a vertical mark on a 100-mm line between 2 anchors: 0 (not at all) and 100 \[complete disability (unable to do any activities)\]. Least Squares (LS) means are calculated using analysis of covariance (ANCOVA) and adjusted for treatment, investigator, and baseline score.
Time frame: Baseline, up to 8 weeks
Population: Intent-to-treat population analysis is determined by the treatment groups to which participants are randomly assigned regardless of treatment received, and includes all participants who do not meet response criteria during Weeks 1-2, have baseline and at least 1 post-baseline VAS-P Score; last observation carried forward (LOCF).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 | Change From Baseline to 8 Weeks in Visual Analog Scale for Pain (VAS-P) | Severity | -4.17 units on a scale | Standard Error 3.45 |
| LY2216684 | Change From Baseline to 8 Weeks in Visual Analog Scale for Pain (VAS-P) | Interference | -9.56 units on a scale | Standard Error 3.611 |
| Placebo | Change From Baseline to 8 Weeks in Visual Analog Scale for Pain (VAS-P) | Severity | -0.91 units on a scale | Standard Error 3.448 |
| Placebo | Change From Baseline to 8 Weeks in Visual Analog Scale for Pain (VAS-P) | Interference | -0.13 units on a scale | Standard Error 3.613 |
Secondary
Change From Baseline to 8 Weeks Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ)
The MGH-SFQ is a 6-item participant-rated scale quantifying sexual interest, arousal (subjective excitement), ability to reach orgasm, erectile function (for males), and overall satisfaction and are scored on a 6-point scale: 1 (greater than normal) to 6 (totally absent); and overall improvement since last medication change is scored on a 6-point scale: 1 (very much improved) to 6 (much worse). Least Squares (LS) means are calculated using analysis of covariance (ANCOVA) and adjusted for treatment, investigator, and baseline score.
Time frame: Baseline, up to 8 weeks
Population: Intent-to-treat population analysis is determined by the treatment groups to which participants are randomly assigned regardless of treatment received, and includes all participants who do not meet response criteria during Weeks 1-2, have baseline and at least 1 post-baseline MGH-SFQ Score.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 | Change From Baseline to 8 Weeks Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ) | Interest | -0.70 units on a scale | Standard Error 0.133 |
| LY2216684 | Change From Baseline to 8 Weeks Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ) | Arousal | -0.74 units on a scale | Standard Error 0.13 |
| LY2216684 | Change From Baseline to 8 Weeks Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ) | Ability to Reach Orgasm | -0.81 units on a scale | Standard Error 0.142 |
| LY2216684 | Change From Baseline to 8 Weeks Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ) | Erectile Function - Males Only | -0.30 units on a scale | Standard Error 0.237 |
| LY2216684 | Change From Baseline to 8 Weeks Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ) | Overall Satisfaction | -0.63 units on a scale | Standard Error 0.141 |
| LY2216684 | Change From Baseline to 8 Weeks Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ) | Overall Improvement | 3.45 units on a scale | Standard Error 0.119 |
| Placebo | Change From Baseline to 8 Weeks Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ) | Overall Satisfaction | -0.48 units on a scale | Standard Error 0.144 |
| Placebo | Change From Baseline to 8 Weeks Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ) | Interest | -0.25 units on a scale | Standard Error 0.136 |
| Placebo | Change From Baseline to 8 Weeks Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ) | Erectile Function - Males Only | -0.48 units on a scale | Standard Error 0.233 |
| Placebo | Change From Baseline to 8 Weeks Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ) | Arousal | -0.27 units on a scale | Standard Error 0.132 |
| Placebo | Change From Baseline to 8 Weeks Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ) | Overall Improvement | 3.62 units on a scale | Standard Error 0.121 |
| Placebo | Change From Baseline to 8 Weeks Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ) | Ability to Reach Orgasm | -0.36 units on a scale | Standard Error 0.144 |
Secondary
Colombia-Suicide Severity Rating Scale (C-SSRS)
Percent of participants with suicidal ideation, behavior and acts based on C-SSRS. The C-SSRS scale captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal behavior: a yes answer to any 1 of 5 suicidal behavior questions (preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide). Suicidal ideation: a yes answer to any 1 of 5 suicidal ideation questions (wish to be dead, and 4 different categories of active suicidal ideation). Suicidal act: a yes answer to actual attempt or completed suicide.
Time frame: Baseline, 8 weeks
Population: Intent-to-treat population analysis is determined by the treatment groups to which participants are randomly assigned regardless of treatment received, and includes all participants who do not meet response criteria during Weeks 1-2, have baseline and at least 1 post-baseline C-SSRS Score.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LY2216684 | Colombia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation | 11.2 percentage of participants |
| LY2216684 | Colombia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Behavior | 0.9 percentage of participants |
| LY2216684 | Colombia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Acts | 0.0 percentage of participants |
| Placebo | Colombia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation | 7.3 percentage of participants |
| Placebo | Colombia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Behavior | 0.0 percentage of participants |
| Placebo | Colombia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Acts | 0.0 percentage of participants |
Other Pre-specified
Change From Baseline to 8 Weeks in Supine Pulse
Pulse is collected while the participant is in the supine position. Least Squares (LS) means are calculated using mixed model repeated measures (MMRM) and adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time frame: Baseline, 8 weeks
Population: Intent-to-treat population analysis is determined by the treatment groups to which participants are randomly assigned regardless of treatment received, and included all participants who have baseline and at least 1 post-baseline supine pulse rate measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 | Change From Baseline to 8 Weeks in Supine Pulse | 6.74 beats per minute (bpm) | Standard Error 0.986 |
| Placebo | Change From Baseline to 8 Weeks in Supine Pulse | 0.65 beats per minute (bpm) | Standard Error 1.038 |
Other Pre-specified
Change From Baseline to 8 Weeks in Supine Systolic and Diastolic Blood Pressure
Blood pressure is collected while the participant is in the supine position. Least Squares (LS) means are calculated using mixed model repeated measures (MMRM) and adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time frame: Baseline, 8 weeks
Population: Intent-to-treat population analysis is determined by the treatment groups to which participants are randomly assigned regardless of treatment received, and includes all participants who have baseline and at least 1 post-baseline supine systolic and diastolic blood pressure measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 | Change From Baseline to 8 Weeks in Supine Systolic and Diastolic Blood Pressure | Systolic Blood Pressure | 3.61 millimeters of mercury (mm Hg) | Standard Error 1.131 |
| LY2216684 | Change From Baseline to 8 Weeks in Supine Systolic and Diastolic Blood Pressure | Diastolic Blood Pressure | 2.67 millimeters of mercury (mm Hg) | Standard Error 0.73 |
| Placebo | Change From Baseline to 8 Weeks in Supine Systolic and Diastolic Blood Pressure | Systolic Blood Pressure | 1.31 millimeters of mercury (mm Hg) | Standard Error 1.195 |
| Placebo | Change From Baseline to 8 Weeks in Supine Systolic and Diastolic Blood Pressure | Diastolic Blood Pressure | 0.77 millimeters of mercury (mm Hg) | Standard Error 0.772 |