A Study Comparing the Efficacy and Safety of Duloxetine and Placebo for the Treatment of Depression in Elderly Patients

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy and safety of duloxetine 60 mg once daily to placebo on depression in elderly patients (greater than or equal to 65 years of age). Patients who do not respond in the first 13 weeks will be eligible for rescue using pre-defined criteria. Patients randomized to duloxetine 60 mg/day meeting the rescue criteria will be increased to 120 mg/day. Patients randomized to the placebo arm meeting the rescue criteria will be assigned to duloxetine 60 mg/day.

Official Title
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Duloxetine Versus Placebo in the Long-Term Treatment of Patients With Late-Life Major Depression

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: duloxetine hydrochloride
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are male or female outpatients at least 65 years of age 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 Mini Mental Score Exam (MMSE) score of at least 20 at Visit 1 Have a degree of understanding such that the patient can 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 Have any prior history of bipolar disorder, panic disorder, psychosis, schizophrenia, or obsessive-compulsive disorder Have any current (within the past 12 months) DSM-IV-TR primary Axis I diagnosis other than MDD Have moderate to severe dementia Have a serious medical illness, including any cardiovascular (CV), hepatic, renal, respiratory, hematologic, endocrinologic, or neurologic disease, or clinically significant laboratory abnormality that is not stabilized or is anticipated to require hospitalization within 6 months, in the opinion of the investigator

Ages Eligible for Study
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Minimum 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: Duloxetine<br> | Drug: duloxetine hydrochloride<br>* Placebo for 1 week (double-blind placebo lead-in), then duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.<br>* Other names: LY248686, Cymbalta;|
| Placebo Comparator: Placebo<br> | Drug: placebo<br>* Placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 13 Weeks in Hamilton Depression Rating Scale (HAMD-17) Maier Subscale | The Maier subscale (Items 1,2,7,8,9,10) represents symptoms of depression. Total subscale scores range from 0 (normal) to 24 (severe). | baseline (Week 1), Week 13 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline on the 30-item Geriatric Depression Scale (GDS) | The 30-item Geriatric Depression Scale (GDS) is a self-administered test of 30 questions to measure the severity of depression. The yes/no questions result in a range of scores from 0 (normal) to 30 (severe depression). | baseline (Week 1), Week 13, Week 25 | 
| Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items | Total Score assess depression severity (scores 0-52). Core, Maier and Bech subscales assess symptoms of depression (scores:0-20=Core; 0-24=Maier; 0-22=Bech). Anxiety/Somatization subscale assesses severity of anxiety (0-18). Retardation subscale assesses dysfunction in mood and work (0-14). Sleep subscale assesses insomnia (0-6). Individual item scores may range from 0-4 or 0-2. Higher numbers indicate more severe symptoms. | baseline (Week 1), Week 13, Week 25 | 
| Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores | The Brief Pain Inventory (severity and interference scales) (BPI) is a self-reported scale that measures the severity of pain and the interference of pain on function. Severity scores: 0 (no pain) to 10 (severe pain) on each question assessing worst pain, least pain, and average pain in past 24 hours, and pain right now. Interference scores: 0 (does not interfere) to 10 (completely interferes) on each question assessing interference of pain in past 24 hours for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. | baseline (Week 1), Week 13, Week 25 | 
| Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores | Numeric Rating Scales (Semantic Differential Scales) for Pain are 6 self-administered scales that assesses experience of overall pain, back pain, headache, shoulder pain, time in pain while awake, and pain interference with daily activities, during the past week. Each item is scored on a numeric 11-point semantic differential scale (0-10) from 0 = no pain to 10 = pain as severe as you can imagine; or 0 = none of the time to 10 = all of the time; or 0 = no interference to 10 = unable to do any activities at all. | baseline (Week 1), Week 13, Week 25 | 
| Patient's Global Impression of Improvement (PGI-I) at 13 Weeks and 25 Weeks | The PGI-Improvement scale is a patient-rated instrument that measures perceived improvement in symptoms. It is a 7-point scale where a score of 1 indicates that the patient is very much improved, a score of 4 indicates that the patient has experienced no change, and a score of 7 indicates that the patient is very much worse. | Week 13, Week 25 | 
| Change From Baseline in the Clinical Global Impression-Severity (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 (Week 1), Week 13, Week 25 | 
| Change From Baseline in the Mini-Mental State Exam (MMSE) | Mini-Mental State Examination (MMSE)is a widely used rating measure of cognitive ability. Scores range from 0 to 30. The MMSE will be used to categorize patients as with or without dementia. Higher number indicates better cognitive ability. Patients with a MMSE score of 20 to 23 will be categorized as having mild dementia, while those with a score of ≥ 24 will be categorized as having no dementia. | baseline (Week 1), Week 9, Week 25 | 
| Change From Baseline in the Quality of Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q-SF) | The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) measures the degree of enjoyment and satisfaction experienced in various areas of daily life. The short version is a self-administered 16 item scale evaluating satisfaction of general activities on a 5-point Likert scale that indicates the degree of enjoyment or satisfaction achieved during the past week (1 = very poor and 5 = very good). | baseline (Week 1), Week 13, Week 25 | 
| Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 | Remission (visitwise binary outcome, yes/no) is defined as HAMD-17 Total Score ≤7 and ≤10. HAMD-17 measures depression severity. The total score can range from 0 (normal) to 52 (severe depression). The visitwise probability of patients meeting criteria for remission (either Total Score ≤7 or ≤10) was analyzed using a categorical, pseudo-likelihood-based repeated measures approach. This analysis included the fixed, categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline score. | Week 13, Week 25 | 
| Probability of Response at Endpoint as Measured by ≥50% Improvement in the HAMD-17 Total Score | Response (visitwise binary outcome, yes/no) is defined as ≥ 50% reduction from baseline in the HAMD-17 total score. HAMD-17 measures depression severity. The total score can range from 0 (normal) to 52 (severe depression). The visitwise probability of patients meeting criteria for response was analyzed using a categorical, pseudo-likelihood-based repeated measures approach. This analysis included the fixed, categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline score. | Week 13, Week 25 | 
| Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 by Medical Comorbidity Severity as Assessed by the Cumulative Illness Rating Scale-Geriatric Version (CIRS-G) | Remission defined as HAMD-17 Total Score ≤7 and ≤10. HAMD-17 measures depression severity. Total score ranges: 0 (normal) to 52 (severe depression). Visitwise probability of patients achieving remission was analyzed using a categorical, pseudo-likelihood-based repeated measures approach. CIRS-G evaluates 14 organ-specific categories using a rating strategy of 0=no problems; 1=current mild problem/past significant problem; 2=moderate disability/morbidity; 3=severe/constant significant disability; and 4=extremely severe/immediate treatment required/end organ failure. Total score ranges: 0 to 56. | Week 13, Week 25 | 
| Probability of Efficacy Onset as Measured by at Least 20% Sustained Reduction From Baseline in the HAMD-17 Maier Subscale at Week 3 | Patients are considered to have met onset (visitwise binary outcome, yes/no) criteria at a particular visit if they had at least 20% reduction from baseline in the HAMD-17 Maier subscale at that visit and at all subsequent visits in the acute phase. Maier subscale measures core symptoms of depression and scores range from 0 (normal) to 24 (severe). The visitwise probability of patients meeting onset criteria was analyzed using a categorical, pseudo-likelihood-based repeated measures approach. | Week 3 | 
| Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) |  | baseline (Week 1), Week 13, Week 25 | 
| Change From Baseline in Pulse Rate |  | baseline (Week 1), Week 13, Week 25 | 
| Change From Baseline in Weight |  | baseline (Week 1), Week 13, Week 25 | 
| Number of Participants With Abnormal Vital Signs and Weight at Any Time During the Study | A patient has a treatment-emergent elevated supine systolic blood pressure if the value is ≥140 with an increase ≥10 from baseline. A patient has a treatment-emergent elevated supine diastolic blood pressure if the value is ≥90 with an increase ≥10 from baseline. A patient has a treatment-emergent elevated supine pulse if the value is ≥100 with an increase ≥10 from baseline. A patient has abnormal weight change if the gain or loss is ≥7% compared to baseline. | Baseline (Week 1) through Week 25 | 
| Number of Participants Experiencing Sustained Hypertension (SH) or Orthostatic Hypotension (OH) | Sustained Hypertension is defined as supine systolic BP >= 140 (or diastolic BP >= 90) mm Hg and increase from baseline (highest value in baseline visit interval) >= 10 mm Hg for 3 or more consecutive visits in postbaseline visit interval. Orthostatic Hypotension is defined as standing diastolic BP at least 10 mm Hg less than the supine diastolic BP or the standing systolic BP at least 20 mm Hg less than the supine systolic BP at any time in postbaseline visit interval and a patient does not meet this criterion at any visit in baseline interval. | baseline (Week 1) through Week 25 | 
| Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation | Adverse Events and Serious Adverse Events leading to study discontinuation. | baseline (Week 1) through Week 25 | 
| Change From Baseline in Laboratory Values - Platelet Count | Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level. | baseline (Week 1), Week 13, Week 25 | 
| Change From Baseline in Laboratory Values - Uric Acid | Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level. | baseline (Week 1), Week 13, Week 25 | 
| Change From Baseline in Laboratory Values - Erythrocyte Count | Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level. | baseline (Week 1), Week 25 | 
| Change From Baseline in Laboratory Values - Hemoglobin, Mean Cell Hemoglobin Concentration (MCHC) | Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level. | baseline (Week 1), Week 25 | 
| Change From Baseline in Laboratory Values - Chloride and Fasting Glucose | Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level. | baseline (Week 1), Week 25 | 
| Number of Participants With Abnormal Laboratory Values - Low Leukocyte Count | The number of participants with abnormal laboratory values at any time during the study period. Results are reported for laboratory analytes that exhibited statistically significantly different proportions of participants who had abnormal values between treatment groups. Statistical significance was considered at the 0.05 level. The lower limit of normal for leukocyte count is 3.8 Billion/Liter. Participants who had a value below that number were considered to have abnormally low leukocyte count. | baseline (Week 1) through Week 13 | 
| Change From Baseline in Electrocardiograms | The Electrocardiogram measures include the following time intervals: QT interval, QT Interval Corrected for Heart Rate Using Fridericia's Formula (QTcF), QT Interval Corrected for Heart Rate Using Bazett's Formula (QTcB), PR interval and QRS interval. | baseline (Week 1), Week 25 | 
| Number of Participants With Successful Treatment Outcome | Successful treatment outcome defined as: Participant completed the study and being in remission (HAMD-17 Total score ≤7 and ≤10) at least for the last two visits (4 weeks)of the study. The HAMD-17 is used to assess the severity of depression. The total score ranges from 0 (not at all depressed) to 52 (severely depressed). | Baseline (Week 1) through Week 25 | 
| Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores | The cognitive assessment battery is composed of four tests: Verbal Learning (score 0-15)and Delayed Recall(score 0-15) test, SDST(Score 0-133),2DCT(score 0-40),Trail Making(Part B)(score 0-180).They are designed to challenge the patient's abilities in the following areas: verbal learning and memory; attention to visually presented material; and working memory and executive function. Composite Cognitive score(0-51)is derived from normalized individual test scores. For Trail Making Test,lower number indicates better cognition. For all other test scores,higher number indicates better cognition. | baseline (Week 1), Week 9, Week 25 |