A Study in Adult Patients With Major Depressive Disorder

Study Overview
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Brief Summary
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The purpose of this study is to assess whether LY2216684 is superior to placebo in the treatment of adult patients with major depressive disorder.

Official Title
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A Randomized, Double-Blind Comparison of LY2216684 and Placebo and Long Term Treatment With LY2216684 in Adult Patients With Major Depressive Disorder

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: Adults age 18-65 years 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 without psychotic features Women of child-bearing potential must test negative for pregnancy and agree to use a reliable method of birth control Grid 17-item Hamilton Rating Scale for Depression (GRID-HAMD17) total score ≥18 at Visit 1 and Visit 2 Clinical global impressions of severity (CGI-S) score ≥4 at Visit 1 and Visit 2 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last 30 days from a clinical trial involving an off-label use of an investigational drug Have previously completed or withdrawn from this study or any other study investigating LY2216684 Have had or currently have any additional ongoing DSM-IV-TR Axis 1 condition other than MDD Have had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 Visit 1 Have an Axis II disorder that would interfere with protocol compliance 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 Women who are pregnant or breast-feeding Have had a lack of response of the current depressive episode to 2 or more adequate courses of antidepressant therapy, or in the judgment of the investigator, considered to have treatment-resistant depression Participants who are judged to be at serious suicidal risk 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 received treatment with a monoamine oxidase inhibitor (MAOI) within 14 days prior to Visit 1 Have a history of severe allergies to more than 1 class of medication or multiple adverse drug reactions Have a history of electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) or psychosurgery within the last year Have a history of any seizure disorder (other than febrile seizures) Require psychotropic medication other than sedative/hypnotic medication for sleep Have a thyroid stimulating hormone (TSH) level outside the established reference range. Are taking or have received treatment with any excluded medication within 7 days prior to Visit 2 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 Visit 1 Have initiated or discontinued hormone therapy within the previous 3 months prior to enrollment

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>10-week Acute Treatment Phase: Day after Week 0=start of 6 milligram (mg) once daily (QD) dosing; Week 1=all participants titrated to 9 mg QD; After Week 1=dose increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug. 1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of acute treatment phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62). | Drug: LY2216684<br>* Flexible Dosing: 6 mg, 9 mg, 12 mg and 18 mg (3 tablets) administered QD for up to 62 weeks<br>|
| Placebo Comparator: Placebo<br>10-week Acute Treatment Phase: 3 tablets QD for 10 weeks 1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684 dose; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62). | Drug: Placebo<br>* Dose: 3 tablets QD for 10 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) at Week 10 | The MADRS measured severity of depressive mood symptoms. The 10-item checklist rating scale was 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 adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. | Baseline, Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline (Week 10) in Montgomery-Asberg Depression Rating Scale (MADRS) at Week 62 | The MADRS measured severity of depressive mood symptoms. The 10-item checklist rating scale was 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 adjusted for investigator, visit, baseline score, and baseline-by-visit. | Baseline (Week 10), Week 62 | 
| Mean Change From Baseline in Sheehan Disability Scale (SDS) Global Functional Impairment at Week 10 | The SDS was completed by the participant and used to assess the effect of the participant's symptoms on their work/social/family life. Total of these 3 items=Global Functional Impairment score; scores ranged from 0 to 30, with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. | Baseline, Week 10 | 
| Mean Change From Baseline (Week 10) in Sheehan Disability Scale (SDS) Global Functional Impairment at Week 62 | The SDS was completed by the participant and used to assess the effect of the participant's symptoms on their work/social/family life. Total of these 3 items=Global Functional Impairment score; scores ranged from 0 to 30, with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit. | Baseline (Week 10), Week 62 | 
| Mean Change From Baseline in Clinical Global Impressions of Severity (CGI-Severity) Scale at Week 10 | CGI-S measured severity of depression at the time of assessment. Scores ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. | Baseline, Week 10 | 
| Mean Change From Baseline (Week 10) in Clinical Global Impressions of Severity (CGI-Severity) Scale at Week 62 | CGI-S measured severity of depression at the time of assessment. Scores ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Least Squares (LS) Means were adjusted for investigator, baseline score, and baseline-by-visit. | Baseline (Week 10), Week 62 | 
| Mean Change From Baseline in the 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) at Week 10 | The QIDS-SR16 was a 16-item participant-rated measure of depressive symptomatology. The total score ranged from 0 to 27, with higher scores indicative of greater severity. Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. | Baseline, Week 10 | 
| Mean Change From Baseline (Week 10) in the 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) at Week 62 | The QIDS-SR16 was a 16-item participant-rated measure of depressive symptomatology. The total score ranged from 0 to 27, with higher scores indicative of greater severity. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit. | Baseline (Week 10), Week 62 | 
| Mean Change From Baseline in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) at Week 10 | The CPFQ was a 7-item participant-rated questionnaire pertaining to a participant's cognitive and physical well-being. It assessed 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 score ranged from 7 to 42. Least Squares (LS) Means were adjusted for treatment, investigator, and baseline score. | Baseline, Week 10 | 
| Mean Change From Baseline (Week 10) in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) at Week 62 | The CPFQ was a 7-item participant-rated questionnaire pertaining to a participant's cognitive and physical well-being. It assessed 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 score ranged from 7 to 42. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit. | Baseline (Week 10), Week 62 | 
| Mean Change From Baseline in the EuroQol Questionnaire-5 Dimension (EQ-5D) United States (US) Index Score at Week 10 | EQ-5D was a generic, multidimensional, health-related, quality of life (Qol) instrument allowing participants to rate their health state in 5 domains: mobility, self-care, usual activities, pain/discomfort, and mood. A single score between 1 and 3 was generated for each domain. For each participant, the outcome rating on the 5 domains was mapped to a single index through an algorithm. The index ranged between 0 and 1, with the higher score indicating a better health state perceived by the participant. Least Squares (LS) Means were adjusted for treatment, investigator, and baseline score. | Baseline, Week 10 | 
| Mean Change From Baseline (Week 10) in the EuroQol Questionnaire-5 Dimension (EQ-5D) United States (US) Index Score at Week 62 | EQ-5D was a generic, multidimensional, health-related, quality of life (Qol) instrument allowing participants to rate their health state in 5 domains: mobility, self-care, usual activities, pain/discomfort, mood. Single score between 1 and 3 was generated for each domain. For each participant, outcome rating on the 5 domains was mapped to a single index through an algorithm. The index ranged between 0 and 1, with higher score indicating a better health state perceived by the participant. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit. | Baseline (Week 10), Week 62 | 
| Mean Change From Baseline in the Fatigue Associated With Depression (FAsD) Patient Reported Outcome (PRO): Average Score at Week 10 | The FAsD was a participant-rated scale with 7 items that asked how often they experience different aspects of fatigue: responses from 1 (Never) to 5 (Always); 9 items that asked how often fatigue impacts various aspects of their lives: responses from 1 (Not at all) to 5 (Very much). Average Score=mean of Items 1-5, 7-12, 14, and 16. Scores ranged from 1 to 5. Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. | Baseline, Week 10 | 
| Mean Change From Baseline (Week 10) in Fatigue Associated With Depression (FAsD) Patient Reported Outcome (PRO): Average Score at Week 62 | The FAsD was a participant-rated scale with 7 items that asked how often they experience different aspects of fatigue: responses from 1 (Never) to 5 (Always); 9 items that asked how often fatigue impacts various aspects of their lives: responses from 1 (Not at all) to 5 (Very much). Average Score=mean of Items 1-5, 7-12, 14, and 16. Scores ranged from 1 to 5. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit. | Baseline (Week 10), Week 62 | 
| Mean Change From Baseline in the Fatigue Associated With Depression (FAsD) Patient Reported Outcome (PRO): Fatigue Experience Average Score at Week 10 | The FAsD was a participant-rated scale with 7 items that asked how often they experience different aspects of fatigue: responses from 1 (Never) to 5 (Always); 9 items that asked how often fatigue impacts various aspects of their lives: responses from 1 (Not at all) to 5 (Very much). Fatigue Experience Average Score=mean of Items 1 to 5, and 7. Scores ranged from 1 to 5. Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. | Baseline, Week 10 | 
| Mean Change From Baseline (Week 10) in Fatigue Associated With Depression (FAsD) Patient Reported Outcome (PRO): Fatigue Experience Average Score at Week 62 | The FAsD was a participant-rated scale with 7 items that asked how often they experience different aspects of fatigue: responses from 1 (Never) to 5 (Always); 9 items that asked how often fatigue impacts various aspects of their lives: responses from 1 (Not at all) to 5 (Very much). Fatigue Experience Average Score=mean of Items 1-5, and 7. Scores ranged from 1 to 5. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit. | Baseline (Week 10), Week 62 | 
| Mean Change From Baseline in the Fatigue Associated With Depression (FAsD) Patient Reported Outcome (PRO): Fatigue Impact Average Score at Week 10 | The FAsD was a participant-rated scale with 7 items that asked how often they experience different aspects of fatigue: responses from 1 (Never) to 5 (Always); 9 items that asked how often fatigue impacts various aspects of their lives: responses from 1 (Not at all) to 5 (Very much). Fatigue Impact Average Score=mean of Items 8-12, 14, and 16. Scores ranged from 1 to 5. Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. | Baseline, Week 10 | 
| Mean Change From Baseline (Week 10) in Fatigue Associated With Depression (FAsD) Patient Reported Outcome (PRO): Fatigue Impact Average Score at Week 62 | The FAsD was a participant-rated scale with 7 items that asked how often they experience different aspects of fatigue: responses from 1 (Never) to 5 (Always); 9 items that asked how often fatigue impacts various aspects of their lives: responses from 1 (Not at all) to 5 (Very much). Fatigue Impact Average Score=mean of Items 8-12, 14, and 16. Scores ranged from 1 to 5. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit. | Baseline (Week 10), Week 62 | 
| Mean Change From Baseline in the Brief Fatigue Inventory (BFI) Global Total Score at Week 10 | The BFI was a participant-rated scale consisting of 9 items: 3 items assessed severity of fatigue at its worst, usual, and now during normal waking hours: 0=no fatigue to 10=fatigue as bad as you can imagine; 6 items assessed the degree to which fatigue has interfered with different aspects of the participant's life during the past 24 hours: 0=does not interfere to 10=completely interferes. The BFI Global Total Score was the mean of the 9 item scores and ranged from 0 to 10. Least Squares (LS) Means were adjusted for treatment, investigator, and baseline score. | Baseline, Week 10 | 
| Mean Change From Baseline (Week 10) in Brief Fatigue Inventory (BFI) Global Total Score at Week 62 | The BFI was a participant-rated scale consisting of 9 items: 3 items assessed severity of fatigue at its worst, usual, and now during normal waking hours: 0=no fatigue to 10=fatigue as bad as you can imagine; 6 items assessed the degree to which fatigue has interfered with different aspects of the participant's life during the past 24 hours: 0=does not interfere to 10=completely interferes. The BFI Global Total Score was the mean of the 9 item scores and ranged from 0 to 10. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit. | Baseline (Week 10), Week 62 | 
| Mean Change From Baseline in the Visual Analogue Scale for Fatigue (VAS-F) Overall Severity and Interference With Daily Activities Scores at Week 10 | The VAS-F was a self-rated assessment with 2 items. For the Overall Severity of Fatigue item, the participant placed a vertical mark on a 100-millimeter (mm) line between 2 anchors (0=not at all to 100=as severe as I can imagine). For the Interference With Daily Activities Due to Fatigue item, the participant placed a vertical mark on a 100 mm line between 2 anchors (0=not at all to 100=complete disability [unable to do any activities]). Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. | Baseline, Week 10 | 
| Mean Change From Baseline (Week 10) in the Visual Analogue Scale for Fatigue (VAS-F) Overall Severity and Interference With Daily Activities Scores at Week 62 | The VAS-F was a self-rated assessment with 2 items. For the Overall Severity of Fatigue item, the participant placed a vertical mark on a 100-millimeter (mm) line between 2 anchors (0=not at all to 100=as severe as I can imagine). For the Interference With Daily Activities Due to Fatigue item, the participant placed a vertical mark on a 100 mm line between 2 anchors (0=not at all to 100=complete disability [unable to do any activities]). Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit. | Baseline (Week 10), Week 62 | 
| Percentage of Participants Reporting Resource Utilization at Week 10 | The Resource Utilization form assessed the frequency and type of medical services that participants have used within the last year, or since the last visit. Resources reported by at least 5% of participants in either treatment group were provided. | Baseline through Week 10 | 
| Percentage of Participants Reporting Resource Utilization at Week 62 | The Resource Utilization form assessed the frequency and type of medical services that participants have used within the last year, or since the last visit. Resources reported by at least 5% of participants in either treatment group were provided. | Baseline (Week 10) through Week 62 | 
| Percentage of Participants With Suicidal Ideation, Behavior, and Acts Based on The Columbia Suicide Severity Rating Scale (C-SSRS) at Week 10 | C-SSRS scale captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Number of participants with suicidal ideation, behavior, and acts were provided. Suicidal ideation=a yes answer to any 1 of 5 suicidal ideation questions (including wish to be dead) and 4 different categories of active suicidal ideation. Suicidal behavior=a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal act=a yes answer to actual attempt or completed suicide. | Baseline through Week 10 | 
| Percentage of Participants With Suicidal Ideation, Behavior, and Acts Based on The Columbia Suicide Severity Rating Scale (C-SSRS) at Week 62 | C-SSRS scale captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Number of participants with suicidal ideation, behavior, and acts were provided. Suicidal ideation=a yes answer to any 1 of 5 suicidal ideation questions (including wish to be dead) and 4 different categories of active suicidal ideation. Suicidal behavior=a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal act=a yes answer to actual attempt or completed suicide. | Baseline (Week 10) through Week 62 | 
| Mean Change From Baseline in Supine Systolic and Diastolic Blood Pressure at Week 10 | Blood pressure was collected while the participant was in the supine position. Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. | Baseline, Week 10 | 
| Mean Change From Baseline (Week 10) in Supine Systolic and Diastolic Blood Pressure at Week 62 | Blood pressure was collected while the participant was in the supine position. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit. | Baseline (Week 10), Week 62 | 
| Mean Change From Baseline in Supine Pulse at Week 10 | Pulse was collected while the participant was in the supine position. Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit. | Baseline, Week 10 | 
| Mean Change From Baseline (Week 10) in Supine Pulse at Week 62 | Pulse was collected while the participant was in the supine position. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit. | Baseline (Week 10), Week 62 | 
| Pharmacokinetic (PK) Parameter: Plasma Concentration of LY2216684 | Blood samples collected from participants that received LY2216684 were measured to determine the plasma LY2216684 concentrations. | Baseline through Week 62 |