A Study of Adjunctive Treatment to Antidepressant Therapy for Adults With Major Depressive Disorder

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Study of Augmentation With LY2216684 for Patients With Major Depressive Disorder Who Are Partial Responders to Selective Serotonin Reuptake Inhibitor Treatment

Conditions
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Depressive Disorder, Major

Intervention / Treatment
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* Drug: LY2216684
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2216684<br> | Drug: LY2216684<br>* 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.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 3 tablets PO QD for up to 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 8 weeks | 
| 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. | Baseline, 8 weeks | 
| 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. | Baseline, up to 8 weeks | 
| 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. | Baseline, 8 weeks | 
| 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. | Baseline, 8 weeks | 
| 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. | Baseline, up to 8 weeks | 
| 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. | Baseline, up to 8 weeks | 
| 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. | Baseline, up to 8 weeks | 
| 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. | Baseline, up to 8 weeks | 
| 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. | Baseline, up to 8 weeks | 
| 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. | Baseline, up to 8 weeks | 
| 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. | Baseline, 8 weeks |