A Study Comparing Duloxetine and Placebo in Assessing Energy and Vitality in Major Depressive Disorder (MDD) Patients

Study Overview
=================
Brief Summary
-----------------
Study F1J-US-HMFS comprises two identical multicenter, 9-month, randomized, placebo-controlled, double-blind, trials (HMFSa and HMFSb). The purpose of this study is to compare the efficacy and safety of Duloxetine 60 milligrams (mg) once daily to placebo on depression in patients aged 18-65. Data from the two trials will be reported in both individual and pooled analyses. Pooling the two studies will allow for increased power to detect differences between duloxetine and placebo on secondary and exploratory objectives. Only one data lock is planned for this study, when all patients have completed all study procedures.

Official Title
-----------------
Duloxetine Versus Placebo in Patients With Major Depressive Disorder (MDD): Assessment of Energy and Vitality in MDD

Conditions
-----------------
Major Depressive Disorder

Intervention / Treatment
-----------------
* Drug: Duloxetine hydrochloride
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female outpatients Aged 18-65 who meet the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria for Major Depressive Disorder (MDD) Have a Montgomery-Asberg Depression Rating Scale (MADRS) total score of at least 22 at visits 1 and 2 Have a Clinical Global Impressions of Severity Scale (CGI-S) score of at least 4 at visits 1 and 2 Have a degree of understanding such that the patient can provide informed consent, complete protocol required assessments and communicate intelligibly with the investigator and study coordinator. Exclusion Criteria: Patients judged clinically to be at serious suicidal risk in the opinion of the investigator Patients who have any prior history of bipolar disorder, psychosis, or schizophrenia Patients who have any current (within the past six months) DSM-IV-TR primary Axis I disorder other than MDD Patients with uncontrolled narrow-angle glaucoma Patients who have a serious medical illness that is in the opinion of the investigator not stabilized or is likely to require intervention, hospitalization, or use of an excluded medication during the course of the study.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>duloxetine 60 milligrams (mg) every day (QD), by mouth (PO) for 3 months, after which may be increased to duloxetine 120 mg QD, PO for 6 months | Drug: Duloxetine hydrochloride<br> <br> * Other names: Cymbalta;|
| Placebo Comparator: B<br>placebo every day (QD), by mouth (PO) for up to 9 months, may be increased to duloxetine 60 mg QD, PO during the first 3 months | Drug: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 8 Weeks in 24-Item Hamilton Depression Rating Scale (HAMD-24) Item 7 (Work and Activities) | Item 7 of the HAMD-24 assesses loss of interest or pleasure in work and activities and is an essential symptom in MDD. Scores range from 0 (no difficulty/no loss) to 4 (difficulty/loss). | baseline, 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 12 Week and 9 Month Endpoints in the 17-Item Hamilton Depression Rating Scale (HAMD-17) Total Score and HAMD-24 Subscales (8 Week Endpoint for Maier Subscale) | The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale (e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe). Please see baseline demographics for subscale total scores. | Baseline, 8 weeks, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in the HAMD-24 Total Score |  | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in the HAMD-24 Item 1:Depressed Mood | Measures depressed mood on a scale of 0 (absent) to 4 (very depressed). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 2:Feelings of Guilt | Measures feelings of guilt on a scale of 0 (absent) to 4 (very guilty). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 3:Suicide | Measures thoughts of suicide on a scale of 0 (absent) to 4 (attempts suicide). | Baseline, 12 weeks, 9 Months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 4:Insomnia Early | Measures early insomnia on a scale of 0 (no difficulty falling asleep) to 2 (complains of nightly difficulty falling asleep). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 5:Insomnia Middle | Measures middle insomnia on a scale of 0 (no difficulty) to 2 (waking during the night). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 6:Insomnia Late | Measures late insomnia on a scale of 0 (no difficulty) to 2 (unable to fall asleep again if gets out of bed). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 9 Month Endpoint in HAMD-24 - Item 7:Work and Activities | Item 7 of the HAMD-24 assesses loss of interest or pleasure in work and activities and is an essential symptom in MDD. Scores range from 0 (no difficulty/no loss) to 4 (difficulty/loss). | Baseline, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 8:Retardation | Measures slowness of thought and speech; impaired ability to concentrate; decreased motor activity on a scale of 0 (normal speech and thought) to 4 (complete stupor). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 9:Agitation | Measures agitation on a scale of 0 (none) to 4 (hand-wringing, nail-biting) | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 10:Anxiety (Psychic) | Measures anxiety on a scale of 0 (no difficulty) to 4 (fears expressed) | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 11:Anxiety (Somatic) | Measures physiological concomitants of anxiety on a scale of 0 (absent) to 4 (incapacitating). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 12:Somatic Symptoms/Gastrointestinal | Measures gastrointestical somatic symptoms on a scale of 0 (none) to 2 (difficulty eating, requires medication for symptoms). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 13:Somatic Symptoms/General | Measures general somatic symptoms on a scale of 0 (none) to 2 (any clear-cut symptoms). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 14:Genital Symptoms | Measures genital symptoms (loss of libido, menstrual disturbances) on a scale of 0 (absent) to 2 (severe). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 15:Hypochondriasis | Measures hypochondriasis on a scale of 0 (not present) to 4 (hypochondriacal delusions). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 16:Loss of Weight | Measures weight loss since last visit on a scale of 0 (no weight loss) to 2 (definite weight loss caused by present illness). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 17:Insight | Measures insight on a scale of 0 (acknowledges being depressed and ill) to 2 (denies being ill at all). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 18A:Diurnal Variation | Measures whether symptoms are worse in morning or evening on a scale of 0 (no variation), 1 (worse in morning), or 2 (worse in evening). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 18B:Diurnal Variation-Severity | Measures the severity of the diurnal variation on a scale of 0 (none) to 2 (severe). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 19: Depersonalization and Derealization | Measures feelings of unreality on a scale of 0 (absent) to 4 (incapacitating). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 20:Paranoid Symptoms | Measures paranoid symptoms on a scale of 0 (none) to 2 (severe). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 21:Obsessional and Compulsive Symptoms | Measures obsessional and compulsive symptoms on a scale of 0 (absent) to 2 (severe). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 22B:Helplessness | Measures feelings of helplessness on a scale of 0 (absent) to 4 (severe). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 23B:Hopelessness | Measures feelings of hopelessness on a scale of 0 (absent) to 4 (expresses feelings of discouragement, despair, and/or pessimism about the future which cannot be dispelled). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in HAMD-24 - Item 24B:Worthlessness | Measures feelings of worthlessness on a scale of 0 (absent) to 4 (severe). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week Endpoint in 30-Item Brief Profile of Mood States (BPOMS) Scale and Subscales (Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment). | The 30-item BPOMS measures mood states and has 6 factors: tension-anxiety, depression-dejection, anxiety-hostility, fatigue, confusion, and vigor. Item scores: 0 (not at all) to 4 (extremely). Each factor scores range from 0 to 20. The Total score is sum of all factor scores minus the factor score for vigor (Total=Ten+Dep+Ang+Fat+Con-Vig). | Baseline, 12 weeks | 
| Change From Baseline to 9 Month Endpoint in 30-Item Brief Profile of Mood States (BPOMS) Scale and Subscales (Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment) | The 30-item BPOMS measures mood states and has 6 factors: tension-anxiety, depression-dejection, anxiety-hostility, fatigue, confusion, and vigor. Item scores: 0 (not at all) to 4 (extremely). Each factor scores range from 0 to 20. The Total score is sum of all factor scores minus the factor score for vigor (Total=Ten+Dep+Ang+Fat+Con-Vig). | Baseline, 9 months | 
| Change From Baseline to 12 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscores | The SDS is completed by the patient and is used to assess the effect of the patient's symptoms on their work/social/family life. Individual item scores range from 0 to 10. Total scores range from 0 to 30 with higher values indicating greater disruption in the patient's work/social/family life. | Baseline, 12 weeks | 
| Change From Baseline to 9 Month Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscores | The SDS is completed by the patient and is used to assess the effect of the patient's symptoms on their work/social/family life. Individual item scores range from 0 to 10. Total scores range from 0 to 30 with higher values indicating greater disruption in the patient's work/social/family life. | Baseline, 9 months | 
| Path Analysis of BPOMS Total Score to Overall Improvement in HAMD-24 Item 7 | Relative contribution of improvement on the mood states, defined by BPOMS total score (calculated from subscales) to overall improvement in work and activities, HAMD-24 item 7 using path analysis. | Over 12 weeks | 
| Path Analysis of BPOMS Total Score to Overall Improvement in HAMD-24 Item 7 - Percent of Total Effect | For Group A, at least one effect was in the opposite direction, percent of total effect was not calculated. | over 12 weeks | 
| Path Analysis of BPOMS Total Score to Overall Improvement in Sheehan Disability Scale (SDS) Total Score | Relative contribution of improvement on the mood states, defined by BPOMS total score (determined from subscales) to overall improvement in SDS total score using path analysis. | over 12 weeks | 
| Path Analysis of BPOMS Total Score to Overall Improvement in SDS Total Score - Percent of Total Effect | For Group A, at least one effect was in the opposite direction, percent of total effect was not calculated. | Over 12 weeks | 
| Change From Baseline to 12 Week and 9 Month Endpoints in 16-Item Quick Inventory of Depressive Symptomatology Self Report (QIDS16SR) Total Score | A 16-item patient-rated measure of depressive symptomatology. The total score ranges from 0 to 27 with higher scores indicative of greater severity. | Baseline, 12 weeks, 9 months | 
| Probability of Remission at 12 Week Endpoint and Sustained Remission at 9 Month Endpoint | Probability of remission as measured by the HAMD17 Total Score ≤ 7 and by the QIDS16SR Total Score ≤ 5. The visitwise percentages of patients meeting criteria in the Acute Therapy Phase for remission (visitwise binary outcome, yes/no) will be analyzed using a categorical, pseudo-likelihood-based repeated measures approach. This analysis will include the fixed, categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline score. | 12 weeks, 9 months | 
| Probability of Response at 12 Week Endpoint | Probability of response as measured by ≥ 50% Improvement in the HAMD17 Total Score and ≥ 50% Improvement in the QIDS16SR Total Score. The visitwise percentages of patients meeting criteria in the Acute Therapy Phase for response (visitwise binary outcome, yes/no) will be analyzed using a categorical, pseudo-likelihood-based repeated measures approach. This analysis will include the fixed, categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline score. | 12 weeks | 
| Change From Baseline to 12 Week and 9 Month Endpoints in Pain Numerical Rating Scale (NRS) | Item 1=Average musculoskeletal pain severity over the last week as measured by an 11-point Likert scale. Scores range from 0 (no pain) to 10 (worst possible pain). Item 7=How much they have been bothered by pain over the last week. Scores range from 0 (not bothered at all)to 10 (extremely bothered). | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoint in the Clinical Global Impression-Severity Scale (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 patients. | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) | A 7-item patitent-rated questionnaire pertaining to a patient's cognitive and physical well-being. It assesses motivation, wakefulness, energy, focus, recall, word-finding difficulty, and mental acuity. Each of the 7 questions is scored on a 6-point scale ranging fom 1 (greater than normal) to 6 (totally absent). Total score ranges from 7 to 42. | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in the Social Adaptation Self-evaluation Scale (SASS) Total Score | A 21-item self-rated scale that evaluates patient social motivation and behavior in depression. Each of the 21 items is scored from 0 (minimal social adjustment) to 3 (maximal social adjustment). Total score ranges from 0 to 60. | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in Blood Pressure | Sitting systolic and diastolic blood pressure. | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in Pulse Rate |  | Baseline, 12 weeks, 9 months | 
| Change From Baseline to 12 Week and 9 Month Endpoints in Weight |  | Baseline, 12 weeks, 9 months | 
| Abnormal Vital Signs at Anytime Over 12 Weeks |  | over 12 weeks | 
| Abnormal Vital Signs at Anytime Over 9 Months |  | over 9 months | 
| Abnormal Vital Signs at 12 Week Endpoint |  | 12 weeks | 
| Abnormal Vital Signs at 9 Month Endpoint |  | 9 months | 
| Statistically Significant Changes in Baseline to 12 Week and 9 Month Endpoints Laboratory Values - Bilirubin, Creatinine, Uric Acid |  | Baseline, 12 weeks, 9 months | 
| Statistically Significant Changes in Baseline to 12 Week and 9 Month Endpoints Laboratory Values - Hematocrit |  | Baseline, 12 weeks, 9 months | 
| Statistically Significant Changes in Baseline to 12 Week and 9 Month Endpoints Laboratory Values - Mean Cell Volume (MCV) |  | Baseline, 12 weeks, 9 months | 
| Statistically Significant Changes in Baseline to 12 Week and 9 Month Endpoints Laboratory Values - Chloride, Urea Nitrogen, Cholesterol, Sodium |  | Baseline, 12 weeks, 9 months | 
| Statistically Significant Changes in Baseline to 12 Week and 9 Month Endpoints Laboratory Values - Platelet Count |  | Baseline, 12 weeks, 9 months | 
| Statistically Significant Changes in Baseline to 9 Month Endpoint Laboratory Values - Alkaline Phosphatase |  | baseline, 9 months | 
| Statistically Significant Changes in Baseline to 9 Month Endpoint Laboratory Values - Hemoglobin |  | Baseline, 9 months | 
| Statistically Significant Abnormal Laboratory Values at Anytime/12 Week Endpoint | The number of participants with statistically significant abnormal lab values at anytime and at 12 week endpoint were the same. | over 3 months | 
| Statistically Significant Abnormal Laboratory Values at Anytime During 9 Months |  | over 9 months | 
| Statistically Significant Abnormal Laboratory Values at 9 Month Endpoint |  | 9 months | 
| Summary of Adverse Events Leading to Discontinuation |  | over 9 months |